On November 18, 2025, the U.S. Food and Drug Administration (FDA) approved epcoritamab-bysp (Epkinly), a bispecific CD20-directed CD3 T-cell engager, in combination with lenalidomide and rituximab for the treatment of patients with relapsed or refractory follicular lymphoma.
In addition, the FDA granted a traditional approval to epcoritamab as monotherapy for the treatment of patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. The FDA granted an accelerated approval to epcoritamab for this indication in 2024.
Combination Regimen
Approval for epcoritamab in combination with lenalidomide and rituximab was based on the randomized, open-label EPCORE FL-1 (Study M20-638; ClinicalTrials.gov identifier NCT05409066) trial, which enrolled 488 patients with relapsed or refractory follicular lymphoma. Patients were randomly assigned (1:1) to receive epcoritamab plus lenalidomide and rituximab or lenalidomide and rituximab alone. Patients had received a median of one prior line of systemic therapy (range, 1–7); 24% and 17% had received two and three or more prior lines, respectively.
Efficacy was established based on progression-free survival and overall response rate, as assessed by an independent review committee using Lugano 2014 criteria. The study demonstrated superiority of both progression-free survival and overall response rate in the epcoritamab arm. The hazard ratio for progression-free survival was 0.21 (95% confidence interval [CI] = 0.13–0.33; P < .0001). The median progression-free survival was not reached (95% CI = 21.9 months to not reached) in the epcoritamab arm and was 11.2 months (95% CI = 10.5 months to not reached) in the control arm. The overall response rate was 89% (95% CI = 84%–93%) in the epcoritamab arm and 74% (95% CI = 68%–79%) in the control arm.
The prescribing information for epcoritamab includes boxed warnings for cytokine-release syndrome and immune effector cell–associated neurotoxicity syndrome, as well as warnings and precautions for infections and cytopenias. Serious adverse reactions occurred in 51% of the patients in the epcoritamab arm, including serious infections in 28%. Cytokine- release syndrome occurred in 24% of patients, including serious cytokine release syndrome in 12%. Immune effector cell–associated neurotoxicity syndrome occurred in 0.8%.
The recommended dosing schedule for epcoritamab in combination with lenalidomide and rituximab consists of epcoritamab administered subcutaneously for up to twelve 28-day cycles, with lenalidomide given on days 1 to 21 of each cycle and rituximab for five cycles. The recommended epcoritamab dosage is a 3 step-up dosage schedule in cycle 1 (0.16 mg on day 1, 0.8 mg on day 8, 3 mg on day 15, and 48 mg on day 22), followed by weekly dosing of 48 mg in cycle 2 and 3, then every-4-week dosing of 48 mg in cycles 4 through 12.
The review for epcoritamab in combination with lenalidomide and rituximab was conducted as a Summary Review and used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Breakthrough Therapy, Priority Review, and Orphan Drug designations.
