Fixed-duration epcoritamab + R-CHOP in patients with newly diagnosed DLBCL and high IPI scores (3–5) led to sustained remissions and disease-free survival beyond 3 years: Results from the EPCORE NHL-2 trial Free

Introduction: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard of care (SOC) for patients with untreated (1L) diffuse large B-cell lymphoma (DLBCL). While R-CHOP is considered curative, approximately one-third of patients relapse, typically within the first 2 years after an initial response. Patients with International Prognostic Index (IPI) scores ≥3 have poorer outcomes, with complete response (CR) rates of ~50% and 5-year PFS rates of ~46%–58% (Ruppert AS, et al. Blood 2020;135:2041–2048). Epcoritamab, a CD3×CD20 bispecific antibody, has demonstrated high response rates as monotherapy or in combination with SOC for patients with 1L DLBCL, regardless of age and fitness. Here, we report efficacy and safety from a 3-year follow-up of patients who received epcoritamab + R-CHOP in the EPCORE® NHL-2 trial (NCT04663347).

Methods: Patients with 1L CD20⁺ DLBCL and IPI score 3–5 received subcutaneous epcoritamab (0.16 mg on cycle 1 [C1] day 1 [D1], 0.8 mg on C1D8, and 48 mg thereafter; QW in C1–4; Q3W in C5–6) + R-CHOP for 6 Cs (21 days each), followed by epcoritamab monotherapy Q4W in 28-day Cs for a total of 1 year of treatment. The primary endpoint was investigator-assessed overall response rate (ORR) per Lugano criteria. Key secondary endpoints included CR rate, duration of response (DOR), duration of CR, PFS, OS, and safety/tolerability. Minimal residual disease (MRD) negativity was also assessed as a secondary endpoint using the exploratory AVENIO Oncology circulating tumor DNA (ctDNA) method (cutoff of <1 mutant molecule per mL).

Results: As of data cutoff (April 9, 2025), 47 patients had received epcoritamab + R-CHOP. Median age was 64 years (range, 19–82), 81% of patients had de novo DLBCL, 34% had bulky disease (≥10 cm), and 6/31 assessed patients had double-/triple-hit DLBCL per central lab. At screening, 57% of patients had IPI score 3 and 38% had IPI score 4–5.

After a median follow-up of 38.8 months (range, 0.8–44.3), the ORR was 98% and CR rate was 85%. An estimated 67% of all responses and 75% of CRs were ongoing at 33 months. High CR rates were observed regardless of IPI score (IPI 3, 86% vs IPI 4-5, 83%). At 33 months, an estimated 80% of patients remained progression-free and 87% were alive; survival outcomes were consistent regardless of IPI score (3 vs 4–5). Efficacy outcomes were also similar across subgroups based on age (≤60 vs >60 years), tumor size (<10 vs ≥10 cm), or cell of origin (germinal center B cell [GCB] vs non-GCB).

By C3D1, 86% (25/29) of MRD-evaluable patients were MRD negative. In patients with longitudinal paired samples, the reduction in ctDNA levels was sustained through C6D1, with a subset of patients showing further decreases. Rapid and sustained reductions in ctDNA were observed regardless of high-risk clinical features, including tumor size (<10 vs ≥10 cm) and IPI score (3 vs 4–5). Additional longitudinal MRD data will be presented.

The majority (94%) of patients completed 6 Cs of R-CHOP, and median duration of epcoritamab was 11.5 months (range, 0.6–13.2). Most (32/47; 68%) patients completed treatment as planned. Reasons that patients did not complete treatment included AEs (11%), progressive disease (9%), withdrawal by patient (6%), COVID-19 control measures (2%), and other (4%; physician decision, incomplete response). At the end of treatment, 30/32 patients who completed treatment as planned had a CR and 1 had a partial response. With a median follow-up for DOR of 25.3 months after treatment, 87% (27/31) of those patients maintained their response.

Safety was consistent with prior reports (Falchi L, et al. Blood 2024;144[Suppl 1]: 581). Serious and grade ≥3 infections primarily occurred in the first 6 months of treatment and then decreased. No new serious infections were reported in the post-treatment period. No new grade 5 AEs were reported.

Conclusions: Fixed-duration epcoritamab + R-CHOP resulted in deep and durable remissions lasting >3 years in most patients with 1L DLBCL and high IPI scores. These findings suggest a long-term survival benefit and potential for high cure rates in this high-risk population. The long-term safety profile was consistent with previous data. Compared with R-CHOP alone, these results are favorable and support further investigation in the ongoing phase 3 EPCORE DLBCL-2 study (NCT05578976) of epcoritamab + R-CHOP versus R-CHOP in newly diagnosed patients with DLBCL.