FDA Approves Epcoritamab for R/R Follicular Lymphoma

The FDA has approved the combination of epcoritamab-bysp (Epkinly), rituximab (Rituxan), and lenalidomide (Revlimid) for the treatment of patients with relapsed or refractory follicular lymphoma.1 The regulatory agency also gave traditional approval to epcoritamab monotherapy for the treatment of patients with relapsed/refractory follicular lymphoma who have received at least 2 prior lines of therapy.

The approval of epcoritamab plus lenalidomide and rituximab was supported by findings from the phase 3 EPCORE FL-1 trial (NCT05409066), which met its coprimary end points of overall response rate (ORR) and progression-free survival (PFS).2 In a preplanned interim analysis, the triplet regimen generated a 79% reduction in the risk of disease progression or death compared with rituximab plus lenalidomide alone (HR, 0.21; 95% CI, 0.13-0.33; P < .0001).1,2 The median PFS was not reached (NR; 95% CI, 21.9 months-NR) in the epcoritamab arm vs 11.2 months (95% CI, 10.5-NR) in the control arm.1 The combination also produced a statistically significant improvement in ORR (P < .0001).2 The ORR was 89% (95% CI, 84%-93%) in the epcoritamab arm vs 74% (95% CI, 68%-79%) in the control arm.1

Notably, the prescribing information for the combination includes warnings and precautions consistent with the known safety profiles of the individual agents. No new safety signals were observed during EPCORE FL-1.

What was the design of the EPCORE FL-1 trial?

EPCORE FL-1 was an open-label, randomized study evaluating subcutaneous epcoritamab in combination with rituximab and lenalidomide vs rituximab and lenalidomide alone in adult patients with relapsed or refractory follicular lymphoma.3,4

Eligible patients were required to have histologically confirmed classic, stage II to IV follicular lymphoma without evidence of histologic transformation to an aggressive lymphoma that was relapsed or refractory to at least 1 prior systemic regimen containing an anti-CD20 monoclonal antibody in combination with chemotherapy. Patients also needed to have CD20-positive disease, have at least 1 measurable lesion, have an ECOG performance status of 0 to 2, be eligible to receive lenalidomide plus rituximab per investigator determination, and have adequate renal function, defined as an estimated creatinine clearance level of at least 50 mL/min.

Patients were randomly assigned 1:1 to receive either:

• Epcoritamab at 48 mg subcutaneously for up to 12, 28-day cycles in combination with rituximab at 375 mg/m² for up to 5 cycles and lenalidomide at 20 mg for up to 12 cycles
• Rituximab plus lenalidomide at the same doses and schedules

The coprimary end points were best ORR and PFS, as assessed by independent review. Secondary end points included complete response (CR) rate; overall survival; minimal residual disease negativity rate; quality of life outcomes; investigator-assessed PFS, best ORR, and CR rate; duration of CR, time to disease progression, and event-free survival.

What additional safety findings were seen in the EPCORE FL-1 trial?

The safety profile of the epcoritamab-based combination was consistent with the established profiles of epcoritamab, rituximab, and lenalidomide.2 Common adverse effects included cytokine release syndrome, fatigue, neutropenia, and infections. Notably, no new safety signals were reported.

What is the regulatory history of epcoritamab, and what are the next steps for the EPCORE FL-1 investigation? 

Epcoritamab previously received accelerated FDA approval in June 2024 as monotherapy for the treatment of adult patients with relapsed or refractory follicular lymphoma who had received at least 2 prior lines of systemic therapy.5 This regulatory decision was based on results from the phase 1/2 EPCORE NHL-1 trial (NCT03625037). In that study, single-agent epcoritamab achieved an ORR of 82% (95% CI, 74.1%-88.2%) in heavily pretreated patients.

The FDA has also granted breakthrough therapy designation to epcoritamab plus rituximab and lenalidomide for the treatment of adult patients with relapsed or refractory follicular lymphoma who have received at least 1 prior line of therapy.2

Additional data from EPCORE FL-1 are planned to be presented at the 2025 ASH Annual Meeting, according to a news release from Genmab and AbbVie.

References

1. FDA approves epcoritamab-bysp for follicular lymphoma indications. FDA. November 18, 2025. Accessed November 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-epcoritamab-bysp-follicular-lymphoma-indications
2. Genmab announces phase 3 EPCORE FL-1 clinical trial met dual primary endpoints in patients with relapsed/refractory (R/R) follicular lymphoma (FL). News release. Genmab. August 7, 2025. Accessed August 7, 2025. https://ir.genmab.com/news-releases/news-release-details/genmab-announces-phase-3-epcorer-fl-1-clinical-trial-met-dual
3. Study of subcutaneous epcoritamab in combination with intravenous rituximab and oral lenalidomide (R2) to assess adverse events and change in disease activity in adult participants with follicular lymphoma (EPCORE FL-1). ClinicalTrials.gov. Updated July 28, 2025. Accessed October 28, 2025. https://clinicaltrials.gov/study/NCT05409066
4. Falchi L, Morschhauser F, Linton K, et al. EPCORE FL-1: phase 3 trial of subcutaneous epcoritamab with rituximab and lenalidomide (R 2) Vs R 2 alone in patients with relapsed or refractory follicular lymphoma. Blood. 2023;142(suppl 1):3053. doi:10.1182/blood-2023-180092
5. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. FDA. June 26, 2024. Accessed October 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-follicular-lymphoma