EPCORE FL-1: Adding Epcoritamab to R2 Delivers “New Benchmark” in Second-Line Follicular Lymphoma

Adding the bispecific antibody epcoritamab (Epkinly; AbbVie/Genmab) to the combination of rituximab (Rituxan) and lenalidomide (Revlimid) offers a huge leap in efficacy for patients who have had their first relapse in follicular lymphoma (FL), one that a trial investigator described as a “new benchmark” in treatment that would make its way into community practice.

Lorenzo Falchi, MD, lymphoma specialist at Memorial Sloan Kettering Cancer Center, presented results early Sunday in press conference for the phase 3 EPCORE FL-1 trial (NCT05409066), which evaluated a fixed-duration regimen of epcoritamab, rituximab, and lenalidomide against rituximab and lenalidomide alone, a combination known as R².

For EPCORE FL-1, 668 patients screened for eligibility across 189 sites in 30 countries, which included those in Africa, Asia, Australia, Europe, North America, and South America. A total of 488 participants were randomly assigned to epcoritamab plus R² arm (243 patients) and R²-only arm (245 patients).

Results for the 2 coprimary end points were as follows:

• Adding epcoritamab to R² offered a 79% progression-free survival (PFS) advantage over R² (HR 0.21; 95% CI, 0.14-31; P <.0001), which was 1 of 2 coprimary end points.^1,2
• Overall response rate also favored the addition of epcoritamab to R² (95% to 79%. With a median follow-up of 14.8 months, the estimated 16-month PFS survival favored the addition of epcoritamab (85.% vs 40.2%0).^1,2

Results were presented in an oral abstract session Sunday and published in The Lancet.² FDA approved the combination with epcoritamab for patients with FL who had been treated with at least 1 prior line of therapy on November 18, 2025.³

In the press conference, Falchi explained that despite the slow progressing nature of FL, once a relapse occurs, the next one will come more quickly without better treatments. “Patients with follicular lymphoma, for the most part, are not cured of their disease, and in particularly after the first line therapy the chance and duration of responses becomes shorter…with each subsequent line of therapy,” he said. “So, there clearly is an unmet need in this space.”

Even as investigators publish data and see approvals come for epcoritamab in second-line treatment of FL, there are already more data showing its potential use in first-line treatment, both in FL and in diffuse large B-cell lymphoma.^4-6

The need for more potent treatments earlier in the course of treatment is balanced by the need for most patients to be treated close to home for as long as possible. With administration of bispecific antibodies moving into community settings, Falchi saw this regimen as the right fit for patients who have just had a relapse.

“Collectively, the benefits were consistent across patient subgroups, including high-risk and low-risk patients, and the safety profile was manageable in this regimen that was administered fully in the outpatient setting,” he said.

Safety data showed there were more adverse events (AEs) in the epcoritamab plus R² arm. Grade 3 or higher AEs were seen in 219 (90%) of the participants vs 161 (68% of those in the R²-only arm. Cytokine release syndrome was low grade with epcoritamab

plus R²; 28 participants had grade 1 CRS (21%), and 7 (5%) had grade 2. All events were resolved.

The fact that epcoritamab plus R² is a fixed duration regimen, given over 12 cycles, follows another trend seen at ASH 2025 toward highlighting combinations that enhance quality of life. The triplet, Falchi said, “is a novel chemotherapy free fixed-duration therapy that is suitable for outpatient administration, and we believe sets a new benchmark as a standard of care.”

References

1. Falci L, Nijland M, Huang H, et al. Primary phase 3 results from the EPCORE FL-1 trial of epcoritamab with rituximab and lenalidomide (R2) versus R2 for relapsed or refractory follicular lymphoma. Presented at: 67^th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Abstract 466.
2. Falci 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. Published online December 7, 2025. https://doi.org/10.1016/S0140-6736(25)02360-8
3. Caffrey M. Epcoritamab with rituximab plus lenalidomide approved for R/R follicular lymphoma in second line. AJMC. November 18, 2025. Accessed December 7, 2025. https://www.ajmc.com/view/epcoritamab-with-rituximab-plus-lenalidomide-approved-for-r-r-follicular-lymphoma-in-second-line
4. Falchi L, 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. Presented at: 67^th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Abstract 1955
5. Cheah C, Duras J, Belada D, et al. Epcoritamab + R mini-CHOP results in 2-year remissions and high-MRD negativity rates in elderly patients with newly diagnosed DLBCL: results from the EPCORE NHL-2 trial. Presented at: 67^th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Abstract 64
6. Fixed-duration epcoritamab in combination with bendamustine + rituximab for first-line treatment of follicular lymphoma: 3-year results from EPCORE NHL-2 arm demonstrate deep and durable responses with manageable safety. Presented at: 67^th American Society of Hematology Annual Meeting & Exposition, December 6-9, 2025; Orlando, FL. Abstract 5357.