Epcoritamab Plus R2 Sustains Efficacy Across Subgroups in R/R Follicular Lymphoma

Epcoritamab (Epkinly) plus lenalidomide and rituximab (R2) produced consistent and durable responses across all clinically relevant patient subgroups in relapsed or refractory (R/R) follicular lymphoma (FL), regardless of comorbidity burden, prior lines of therapy, disease risk, or bulky disease status, according to post hoc subgroup analyses from the phase 3 EPCORE FL-1 trial (NCT05409066) presented at the 2026 European Hematology Association Annual Congress.^1,2

In the overall intention-to-treat (ITT) population of 488 randomly assigned patients, epcoritamab plus R2 (n = 243) demonstrated an overall response rate (ORR) of 95% and a complete response rate (CRR) of 83%, compared with 79% and 50%, respectively, with R2 alone (n = 245). The PFS HR in the overall ITT population was 0.21 (95% CI, 0.14-0.31), representing a 79% reduction in the risk of disease progression or death.^1,2

The PFS benefit was consistent across all age subgroups. In patients younger than 70 years, the ORR was 96% and the CRR was 84% with epcoritamab plus R2, compared with 78% and 50% with R2 alone (HR, 0.19; 95% CI, 0.12-0.31). In patients aged 70 or older, the ORR was 91% and the CRR was 79%, whereas with R2 alone, those rates were 81% and 50% (HR, 0.29; 95% CI, 0.14-0.60), confirming that older patients derive a fairly comparable benefit.^1,2

Comorbidity burden, as assessed by the NHL-5 comorbidity index, did not diminish the epcoritamab benefit. In patients with low NHL-5 scores, the ORR was 94% and the CRR was 81%, compared with 76% and 50% with R2 alone (HR, 0.27; 95% CI, 0.17-0.42). In patients with high or intermediate NHL-5 scores, the PFS HR was 0.14 (95% CI, 0.06-0.29), indicating a more pronounced benefit in those with greater comorbidity burden.

The benefit was maintained across prior-line-of-therapy subgroups. In patients with 1 prior line of therapy (LOT), the ORR was 96% and the CRR was 87%, compared with 80% and 53% with R2 alone (HR, 0.20; 95% CI, 0.12-0.34). In patients with 2 or more prior LOTs, the ORR was 94% and the CRR was 77%, compared with 78% and 45% (HR, 0.24; 95% CI, 0.13-0.42).

Baseline Follicular Lymphoma International Prognostic Index (FLIPI) score did not influence the treatment benefit. In patients with FLIPI 0 to 2, the ORR was 96.5% and the CRR was 86.6% compared with 84.8% and 62.1% with R2 alone (HR, 0.18; 95% CI, 0.10-0.33). In patients with FLIPI 3 to 5, the ORR was 93.0% and the CRR was 77.0%, compared with 72.6% and 35.4% (HR, 0.25; 95% CI, 0.15-0.42).

POD24 status did not influence outcomes. In patients without POD24, the ORR was 96% and the CRR was 85.5%, compared with 85% and 57.6% with R2 alone (HR, 0.17; 95% CI, 0.09-0.32). In patients with POD24, the ORR was 95% and the CRR was 80%, compared with 70% and 39% (HR, 0.22; 95% CI, 0.13-0.37).

The presence of bulky disease or double-refractory status did not negate the PFS benefit. In patients with bulky disease, the ORR was 96% and the CRR was 79% compared with 62% and 23% with R2 (HR, 0.12; 95% CI, 0.05-0.28); in patients with nonbulky disease, the HR was 0.26 (95% CI, 0.17-0.41). For patients with double-refractory disease, the ORR was 95% and the CRR was 79%, compared with 69% and 35% (HR, 0.23; 95% CI, 0.13-0.39); in patients without double-refractory disease, the HR was 0.19 (95% CI, 0.11-0.34).

The PFS benefit was maintained even when lenalidomide dose modifications were required, according to relative dose intensity (RDI) analysis. In patients receiving lenalidomide RDI greater than 70%, the HR was 0.13 (95% CI, 0.06-0.25), and in those receiving RDI of 50% or less, the HR remained 0.28 (95% CI, 0.15-0.51). A comprehensive forest plot confirmed PFS HRs consistently well below 1.0 across all subgroups.

“The EPCORE FL-1 trial, bolstered by this subgroup analysis, established fixed-duration epcoritamab in combination with R2 for relapsed or refractory follicular lymphoma,” Benoît Tessoulin, MD, PhD, Nantes University School of Medicine and University Hospital, France, stated in a news release. “It delivers consistent efficacy and a manageable safety profile, regardless of comorbidity burden.”

Safety Profile

The safety profile of epcoritamab plus R2 was generally manageable across all subgroups with no new safety signals.¹ Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 89% of patients younger than 70 years and 93% of those aged 70 or older in the epcoritamab arm vs 64% and 76% with R2 alone. Grade 3 or higher TEAEs were similarly high across NHL-5–low and NHL-5–high or intermediate patients (90% in both groups) in the epcoritamab arm. Although neutropenia and infections were more frequent in patients receiving lower lenalidomide doses, the PFS benefit was maintained, consistent with standard practice in which lenalidomide dose reductions are used to manage adverse events while preserving efficacy.¹

Study Design and Patient Characteristics

EPCORE FL-1 (NCT05409066) is a global, randomized, open-label trial in adult patients with CD20-positive R/R FL who had received at least 1 prior anti-CD20–based regimen. Patients were randomly assigned 1:1 to epcoritamab 48 mg subcutaneously plus R2, or to R2 alone, for 12 fixed-duration 28-day cycles. Dual primary end points were ORR and PFS by independent review committee. The data cutoff was May 24, 2025, with a median follow-up of 14.8 months.¹ Epcoritamab is approved in the United States, Brazil, and China and received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use in May 2026 for this indication.¹

“The EPCORE FL-1 subgroup analysis demonstrated consistent and deep responses with a manageable safety profile across all patient characteristics, including varying risk profiles and lenalidomide dosing schedule, which validate the potential of the combination therapy,” Judith Klimovsky, MD, executive vice president and chief development officer of Genmab, stated in a news release.¹ “These data strongly reinforce our belief that epcoritamab, combined with rituximab and lenalidomide, is poised to transform the treatment paradigm, offering a highly effective and broadly accessible option for relapsed or refractory follicular lymphoma.”

References

1. Genmab presents EPCORE FL-1 subgroup data demonstrating consistent efficacy and safety results for epcoritamab in combination with rituximab and lenalidomide (R2) across relapsed or refractory (R/R) follicular lymphoma (FL) patients. News release. Genmab A/S. June 11, 2026. Accessed June 11, 2026. https://sg.finance.yahoo.com/news/genmab-presents-epcore-fl-1-144500106.html

2. Nijland M, Falchi L, Linton K, et al. Clinically relevant subgroup analysis from the randomized phase 3 EPCORE FL-1 trial: treatment effect of epcoritamab with lenalidomide and rituximab in R/R follicular lymphoma. Presented at: 31st European Hematology Association Annual Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S229.