FDA Approves Epcoritamab Plus Lenalidomide/Rituximab in R/R Follicular Lymphoma

The FDA has approved epcoritamab-bysp (Epkinly) with lenalidomide (Revlimid) and rituximab (Rituxan; together R2) for the treatment of relapsed or refractory follicular lymphoma (FL).

With this approval, the FDA has also approved epcoritamab as monotherapy for relapsed or refractory FL following 2 or more lines of systemic therapy, a setting in which the bispecific T-cell engager (BiTE) antibody was granted accelerated approval in June 2024.

The agent’s approval with lenalidomide and rituximab was supported by data from the randomized, open-label phase 3 EPCORE FL-1 trial (NCT05409066), where 488 patients with relapsed or refractory FL were randomized 1:1 to receive either epcoritamab with R2 or R2 alone. The epcoritamab arm had superior progression-free survival (PFS) and overall response rate (ORR).

The addition of epcoritamab reduced the risk of death or disease progression by 79% (hazard ratio, 0.21; 95% CI, 0.13-0.33); P < .0001), and the median PFS was not reached (95% CI, 21.9-NR) vs 11.2 months (95% CI, 10.5-NR) in the R2 arm. The ORR was 89% (95% CI, 84%-93%) in the epcoritamab arm and 74% in the control arm.

Understanding the Safety and Dosing of Epcoritamab

Epcoritamab’s prescribing information includes warnings for cytokine release system (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) along with warnings and precautions for infections and cytopenias. Serious adverse effects (AEs) occurred in 51% of patients receiving epcoritamab, and 28% experienced serious infections. Patients had a median of 1 prior line of systemic therapy (range, 1-7).

The recommended dosage of epcoritamab when combined with R2 is subcutaneous epcoritamab for up to 12 28-day cycles along with lenalidomide on days 1 to 21 of each cycle with rituximab for 5 cycles.

Step-up dosing is recommended, with 0.16 mg on day 1, 0.8 mg on day 8, 3 mg on day 15, and 48 mg on day 22. This should be followed by weekly dosing of 48 mg in cycles 2 and 3, then each 4-week dosing of 48 mg in cycles 4 through 12.

Epcoritamab Monotherapy

The BiTE’s accelerated approval as a monotherapy was based on findings from the EPCORE NHL-1 trial (NCT03625037), which saw solo epcoritamab produce an ORR of 82% (95% CI, 74.1%-88.2%), a complete response rate of 60% (95% CI, 50.8%-68.4%), and a partial response rate of 22% (95% CI, 15.2%-30.3%).

In this trial, the most common AEs experienced by 10% or more of patients with relapsed or refractory FL who received epcoritamab included cytokine release syndrome (all grade, 49%; grade 3/4, 0%), injection site reactions (58%; 0%), fatigue (37%; 5%), pyrexia (26%; 2%), edema (17%; 0%), COVID-19 (40%; 19%), upper respiratory tract infection (29%; 2%), pneumonia (17%; 13%), urinary tract infection (13%; 5%), herpesvirus infection (12%; 1.6%), musculoskeletal pain (28%; 0.8%), arthralgia (14%; 0.8%), rash (28%; 0%), diarrhea (26%; 1.6%), nausea (17%; 0%), abdominal pain (17%; 0.8%), constipation (16%; 0%), mucositis (12%; 0%), cough (20%; 0%), dyspnea (17%; 0%), headache (20%; 0%), neurological changes (13%; 0%), peripheral neuropathy and paresthesia (13%; 1.6%), dizziness (11%; 0%), insomnia (13%; 0%), and renal insufficiency (10%; 1.6%).

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. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. FDA. June 26, 2024. Accessed June 26, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-follicular-lymphoma
3. Epkinly. Prescribing information. Genmab US, Inc; 2024. Accessed June 26, 2024. https://www.genmab-pi.com/prescribing-information/epkinly-pi.pdf