Introduction: Dose-attenuated rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-mini-CHOP) is a standard of care (SOC) for patients with newly diagnosed (1L) diffuse large B-cell lymphoma (DLBCL) unable to receive full-dose R-CHOP due to age or comorbidities. However, outcomes following R-mini-CHOP remain suboptimal, with overall response rates (ORR) of 60%–80%, complete response (CR) rates of 40%–60%, 2-year PFS of 51%, and 2-year OS of 60% (Al-Sarayfi D, et al. Am J Hematol 2024;99:216–222). In the EPCORE® NHL-2 trial (phase 1b/2; NCT04663347), epcoritamab, a CD3×CD20 bispecific antibody, combined with R-mini-CHOP demonstrated promising efficacy and manageable safety in elderly patients with 1L DLBCL ineligible for full-dose R-CHOP (Leslie LA, et al. Blood 2024;144[Suppl 1]:3106). Here, we present results from this cohort after 2 years of follow-up.

Methods: Adults with newly diagnosed CD20+ DLBCL who were ineligible for full-dose R-CHOP due to age ≥75 years or age ≥65 years with comorbidities, received fixed-duration subcutaneous epcoritamab 48 mg (QW, cycle(s) [C] 1–2 [21 days each]; Q3W, C3–6 [21 d each]; Q4W, C7–8 [28 d each]; with step-up dosing in C1 [0.16 mg on C1 day 1 (D1) and 0.8 mg on C1D8]) + R-mini-CHOP (Q3W, C1–6). The primary endpoint was ORR per Lugano criteria. Minimal residual disease (MRD) negativity was assessed as a secondary endpoint using the exploratory AVENIO Oncology circulating tumor DNA (ctDNA) method; MRD negativity was defined as <1 mutant molecule per mL.

Results: As of April 9, 2025, 28 patients had received epcoritamab + R-mini-CHOP. Median age was 81 years (range, 74–90), 89% of patients had de novo DLBCL, 46% had germinal center B-cell (GCB) and 39% had non-GCB, 68% had International Prognostic Index (IPI) scores 3–5, 64% had elevated LDH, and 39% had bulky disease (≥7 cm). Most patients (22/28; 79%) completed treatment as planned, and median relative dose intensity of R-mini-CHOP was ≥94%.

With a median follow-up of 28.0 months (range, 2.8–34.5), the ORR was 89% and the CR rate was 86%. Median duration of response and duration of CR were not reached (NR) at data cutoff. At 2 years, an estimated 78% of all responses and 78% of CRs were maintained. Median PFS and median OS were NR. The estimated 2-year PFS and OS rates were 76% and 82%, respectively, at data cutoff. 20/22 patients who completed treatment had a CR at end of treatment; with a median follow-up for duration of CR of 22.6 months after treatment end, 18/20 (90%) remained in CR at data cutoff.

MRD negativity was reported for 20 (95%) of the 21 patients evaluable for MRD at any time; 16/20 were MRD negative by C3D1. Among patients who were MRD negative at C3D1 and had paired longitudinal samples, 86% (12/14) sustained their MRD negativity through C6D1. High rates of MRD negativity were observed among high-risk subgroups, such as patients with bulky disease (8/9, 89%) and IPI score 3-5 (14/15, 93%).

Safety was consistent with prior reports (Leslie LA, et al. Blood 2024;144 [Suppl 1]:3106). Eight (29%) patients experienced a grade ≥3 infection, with the majority (in 6/8 patients) occurring within the first 6 cycles of treatment. Treatment-emergent AEs led to epcoritamab discontinuation in 3 (11%) patients, including grade 2 rhinitis, grade 2 cytokine release syndrome, and grade 5 confusional state and cytomegalovirus infection reactivation in a patient aged 90 years also diagnosed with acute cerebrovascular accident.

Conclusions: Fixed-duration epcoritamab + R-mini-CHOP led to high ORR and CR rates, rapid and sustained MRD negativity, and durable remissions in elderly patients with newly diagnosed DLBCL ineligible for full-dose R-CHOP. Despite the elderly population, outcomes compare favorably with historical outcomes of R-mini-CHOP alone. These results, along with those from other arms of the trial, support combinations of epcoritamab with SOC across a range of disease settings and patient populations.

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2025
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