Fixed-Duration Epcoritamab + R-CHOP Induces High Complete Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Withhigh-Risk Features: Long-Term Results from the Epcore NHL-2 Trial

Introduction: Epcoritamab, a CD3xCD20 bispecific antibody, has been approved as a single agent for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma after ≥2 lines of systemic therapy based on results from the phase 1/2 EPCORE^® NHL-1 trial (NCT03625037). Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‑CHOP) is an accepted standard treatment for patients with previously untreated (1L) DLBCL; however, relapse rates can reach 40%. High-risk patients with International Prognostic Index (IPI) 3–5 and patients with double‑hit/triple-hit lymphoma have suboptimal complete response (CR) rates and long‑term outcomes. Following R-CHOP, 5-y estimates of progression-free/overall survival (OS) decreased from 81%/88% in patients with IPI 0–1 to 67%/76% for IPI 2, 58%/67% for IPI 3, and 46%/54% for IPI 4–5 (Ruppert et al, Blood 2020), suggesting a need for novel regimens to increase cure rates for newly diagnosed patients with DLBCL with high-risk features. Previously, in arm 1 of the EPCORE NHL‑2 trial (phase 1b/2; NCT04663347), the combination of epcoritamab + R‑CHOP showed encouraging response rates and a manageable safety profile in 1L DLBCL, including in high-risk patients (Clausen et al, EHA 2023). Here, we present long-term follow-up beyond 2 y, including in subgroups, and minimal residual disease (MRD) analyses for the first time.

Methods: Adults with 1L CD20⁺ DLBCL and IPI ≥3 received subcutaneous epcoritamab (QW in cycles 1–4; Q3W in cycles 5–6) + R-CHOP for 6 cycles (21 d each) followed by epcoritamab monotherapy Q4W in 28‑d cycles for up to 1 y. The primary endpoint was overall response rate (ORR) based on best overall response per Lugano criteria. MRD negativity was assessed as a secondary endpoint using the exploratory AVENIO ctDNA method. Double-hit/triple-hit status was assessed by central lab.

Results: As of May 15, 2024, 47 patients had received epcoritamab 48 mg + R‑CHOP, with a median follow-up of 27.4 mo (range, 0.8–33.9). All patients had IPI 3–5 at screening, 6 (21%) of 28 patients with evaluable tissue available had double-hit/triple-hit DLBCL, and 16 patients (34%) had bulky disease (>10 cm). The median time from diagnosis to first dose was 4 wk (range, 1.3–60.4). Median relative dose intensity for all R‑CHOP components was ≥95%.

Among 46 evaluable patients, the ORR was 100%, with a CR rate of 87%. Most patients (96%; 44/46) completed 6 cycles of R-CHOP; 91% (40/44) had a CR, and the 2 patients who did not complete 6 cycles of R-CHOP had a partial response. Notably, patients with double-hit/triple-hit DLBCL had a CR rate (83%; 5/6) similar to the overall population. An estimated 74%/87% of patients remained progression free/alive at 24 mo. Durable responses were observed, with an estimated 83% of patients with CR remaining in CR at 24 mo. MRD negativity (cutoff, <1 mutant molecule per mL) was observed in 91% of evaluable patients (30/33).

The most common treatment-emergent AEs (TEAEs) of any grade (G) were neutropenia (70%), anemia (68%), CRS (60%), fatigue (49%), nausea (47%), pyrexia (43%), and injection-site reaction (40%). Four patients (9%) discontinued epcoritamab due to TEAEs; G5 TEAEs occurred in 2 patients (COVID-19 and septic shock). CRS events were mostly low grade (45% G1, 11% G2, 4% G3) and mainly occurred after the first full dose; all resolved, and none led to discontinuation. ICANS occurred in 2 patients (G1, n=1; G2, n=1) and resolved in a median of 2.5 d without leading to discontinuation.

Conclusions: Fixed-duration epcoritamab + R-CHOP induced deep, durable CRs (24-mo estimated duration of CR, 83%) and high rates of MRD negativity (91% of evaluable patients), leading to long-term remissions (24-mo estimated OS, 87%) beyond 2 y in patients with 1L DLBCL, including those with high-risk features, such as double-hit/triple-hit disease. These results suggest a high curative potential for this potent first-line combination. The safety profile was manageable, with no new safety signals detected, underscoring the combinability of epcoritamab with standards of care in 1L DLBCL. These data compare favorably with R-CHOP alone in this setting and further support the ongoing phase 3 trial of epcoritamab + R-CHOP in 1L DLBCL(NCT05578976).