Fixed-duration epcoritamab (Epkinly) plus lenalidomide (Revlimid) and rituximab (Rituxan) produced superior responses and progression-free survival (PFS) over lenalidomide and rituximab alone across clinically relevant subgroups of patients with relapsed/refractory follicular lymphoma, including those with high-risk features, in post hoc subgroup analyses from the phase 3 EPCORE FL-1 trial (NCT05409066) presented at the 2026 EHA Congress.1
The PFS benefit with epcoritamab plus lenalidomide and rituximab vs lenalidomide and rituximab alone was maintained regardless of patient age (HR for patients < 70 years of age, 0.19 [95% CI, 0.12-0.31]; HR for patients ≥ 70 years of age, 0.29 [95% CI, 0.14-0.60]). Among patients younger than 70 years of age (n = 185 vs n = 171, respectively), the overall response rates (ORRs) were 96% vs 78%, and the complete response (CR) rates were 84% vs 50%. In patients ages 70 years of age or older (n = 58 vs n = 74, respectively), the ORRs were 91% vs 81%, and the CR rates were 79% vs 50%.
The NHL-5 comorbidity score was used to stratify patients into low vs high/intermediate groups. Epcoritamab plus lenalidomide and rituximab outperformed lenalidomide and rituximab alone in both strata: NHL-5–low patients (n = 166 vs n = 149, respectively) achieved ORRs of 94% vs 76% and CR rates of 81% vs 50%, respectively. PFS outcomes favored the triplet in this population (HR, 0.27; 95% CI, 0.17-0.42). NHL-5–high/intermediate patients (n = 77 vs n = 96, respectively) experienced respective ORRs of 97% vs 84% and CR rates of 86% vs 49%. PFS outcomes also favored the triplet in this group (HR, 0.14; 95% CI, 0.06-0.29).
Efficacy was similarly favorable in the triplet arm across prior line of therapy subgroups. In patients with 1 prior line of therapy (n = 145 vs n = 141, respectively), the ORRs were 96% vs 80%, the CR rates were 87% vs 53%, and the hazard ratio for PFS was 0.20 (95% CI, 0.12-0.34). In patients with 2 or more prior lines of therapy (n = 98 vs n = 104), the ORRs were 94% vs 78%, the CR rates were 77% vs 45%, and the HR for PFS was 0.24 (95% CI, 0.13-0.42).
Baseline Follicular Lymphoma International Prognostic Index (FLIPI) score did not attenuate the PFS benefit seen with the triplet (FLIPI 0 to 2, HR, 0.18 [95% CI, 0.10-0.33]; FLIPI 3 to 5, HR, 0.25 [95% CI, 0.15-0.42]), nor did progression of disease 2 years or less from the initiation of frontline therapy (POD24; no POD24, HR, 0.17 [95% CI, 0.09-0.32]; POD24, HR, 0.22 [95% CI, 0.13-0.37]). Epcoritamab plus lenalidomide and rituximab also demonstrated superior PFS over lenalidomide and rituximab alone regardless of bulky disease (bulky, HR, 0.12 [95% CI, 0.05-0.28]; non-bulky, HR, 0.26 [95% CI, 0.17-0.41]) and double refractory status (double refractory, HR, 0.23 [95% CI, 0.13-0.39]; not double refractory, HR, 0.19 [95% CI, 0.11-0.34]).
“In patients with reduced lenalidomide relative dose intensity, the PFS was improved with epcoritamab plus lenalidomide and rituximab compared with lenalidomide and rituximab alone, reinforcing that treatment benefit is maintained despite dose modifications,” Benoit Tessoulin, MD, PhD, of the Nantes University School of Medicine & University Hospital in France, stated in the presentation of the data.
What was the design of EPCORE FL-1?
EPCORE FL-1 enrolled adult patients with histologically confirmed, CD20-positive relapsed/refractory follicular lymphoma that was grade 1 to 3A and stage II to IV. Patients needed to have received at least 1 prior treatment, including an anti-CD20 monoclonal antibody plus an alkylating agent, and needed to meet at least 1 GELF criterion. Patients were randomly assigned 1:1 to receive epcoritamab at 48 mg subcutaneously (step-up dosing in cycle 1, then weekly in cycles 2 to 3, then every 4 weeks in cycles 4 to 12) plus rituximab at 375 mg/m2 for 5 cycles (cycle 1 weekly, cycles 2 to 5, every 4 weeks) and lenalidomide at 20 mg (on days 1 to 21 of 12 cycles) vs lenalidomide and rituximab alone.
What efficacy findings from EPCORE FL-1 have been previously reported?
At a data cutoff of May 24, 2025, and a median follow-up of 14.8 months (interquartile range, 11.4-19.0), in the intent-to-treat population, epcoritamab plus lenalidomide and rituximab (n = 243) produced an ORR of 95% (95% CI, 92%-97%) and a CR rate of 83% (95% CI, 77%-87%), vs an ORR of 79% (95% CI, 74%-84%; P < .0001) and a CR rate of 50% (95% CI, 43%-56%; P < .0001) with lenalidomide and rituximab alone (n = 245).2 The median PFS outcomes strongly favored the epcoritamab arm (HR, 0.21; 95% CI, 0.14-0.31; P < .0001), representing a 79% reduction in the risk of disease progression or death. These results, previously published in The Lancet, served as the backdrop for the EHA 2026 subgroup analyses examining whether the treatment benefit extended across age, comorbidity burden, prior lines of therapy, FLIPI score, POD24 status, bulky disease, and double refractory status.1,2
EPCORE-NHL 1 Trial Subgroup Analysis Key Takaways
- The PFS benefit seen with epcoritamab plus lenalidomide and rituximab vs lenalidomide and rituximab alone was consistent across all 7 clinically relevant subgroups examined, including patients with POD24, bulky disease, double refractory status, and high comorbidity burden.
- The PFS improvement was maintained in patients who received reduced lenalidomide dose intensity, including those with a lenalidomide relative dose intensity of less than 50% (HR, 0.28; 95% CI, 0.15-0.51).
- The safety profile of epcoritamab plus lenalidomide and rituximab was generally manageable across age and comorbidity subgroups, with no new or unexpected signals identified.
Did lenalidomide dose intensity affect the benefit of epcoritamab?
Lenalidomide relative dose intensity, defined as the actual lenalidomide dose received as a percentage of the planned dose over 12 cycles, was assessed in 3 relative dose intensity subgroups: less than 50%, 70% or lower, and greater than 70%.1 The PFS benefit with epcoritamab plus lenalidomide and rituximab over lenalidomide and rituximab alone was maintained across all 3 strata, with respective hazard ratios of 0.28 (95% CI, 0.15-0.51), 0.25 (95% CI, 0.15-0.41), and 0.13 (95% CI, 0.06-0.25). The investigators noted that the treatment benefit with the epcoritamab-containing regimen was maintained even when patients required lenalidomide dose modifications.
What was the safety profile of epcoritamab plus lenalidomide and rituximab across subgroups of patients with follicular lymphoma?
The safety profile of epcoritamab plus lenalidomide and rituximab was generally manageable across age-defined subgroups. Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 89% and 93% of patients younger than 70 years of age and those at least 70 years of age, respectively, in the epcoritamab arm, vs in 64% and 76% of patients in these respective age groups in the lenalidomide and rituximab arm. Grade 3 or higher neutropenia was reported in 71% of younger and 62% of older patients who received epcoritamab, vs 40% and 47% of those who received lenalidomide and rituximab alone. Serious TEAEs occurred in 54% of younger and 60% of older patients in the epcoritamab arm. TEAEs leading to discontinuation were reported in 15% and 31% of patients in the younger and older epcoritamab subgroups, respectively.
The safety profile of the triplet remained manageable in patients with higher comorbidity burden. Among NHL-5 high/intermediate patients receiving epcoritamab plus lenalidomide and rituximab, grade 3 or higher TEAEs occurred in 90%, serious TEAEs were reported in 56%, fatal TEAEs were seen in 4%, and grade 3 or higher neutropenia occurred in 73%. These respective rates were 69%, 37%, 5%, and 41% in the lenalidomide/rituximab alone NHL-5 high/intermediate arm.
“Collectively, these findings further support fixed-duration epcoritamab plus lenalidomide and rituximab as a new standard of care in second- [and later-line patients with] follicular lymphoma, with the potential to improve treatment expectations across a broad patient population,” Tessoulin concluded.
Disclosures: Tessoulin reported receiving honoraria from AbbVie, AstraZeneca, Incyte, Bristol-Myers Squibb, Eli Lilly, and Johnson & Johnson.
References
- 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: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S229.
- Falchi L, Nijland M, Huang H, et al. Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial. Lancet. 2026;407(10524):161-173. doi:10.1016/S0140-6736(25)02360-8
