FDA Approves Epcoritamab Combo in R/R Follicular Lymphoma

The News

The FDA has approved subcutaneous epcoritamab-bysp (Epkinly) in combination with rituximab (Rituxan) and lenalidomide (Revlimid) for the treatment of adult patients with relapsed/refractory follicular lymphoma, according to a news release from the agency.¹ The agency also granted traditional approval to epcoritamab monotherapy for those with relapsed/refractory follicular lymphoma after at least 2 prior lines of systemic therapy.

Supporting Data

The approval for the epcoritamab-based regimen was supported by findings from the phase 3 EPCORE FL-1 trial (NCT05409066), in which investigators evaluated the combination vs rituximab and lenalidomide alone in patients with CD20-positive stage II, III, or IV classic follicular lymphoma and no evidence of histologic transformation to an aggressive lymphoma. Findings from a preplanned interim analysis of EPCORE FL-1 were previously published in a news release and are to be submitted for presentation at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.²

The findings revealed that the trial met its coprimary end points of objective response rate (ORR; P <.0001) and progression-free survival (PFS; HR, 0.21; 95% CI, 0.13-0.33; P <.0001) in this patient population. Although the median PFS was not reached (NR; 95% CI, 21.9-NR) in this population, a 79% reduction in the risk of disease progression or death was observed with the epcoritamab combination vs rituximab/lenalidomide alone. The median PFS in the latter arm was 11.2 months (95% CI, 10.5-NR).

Additionally, the ORR was 89% (95% CI, 84%-93%) in the epcoritamab arm vs 74% (95% CI, 68%-79%) in the control arm.

Expert Perspective

“What is important from this long-term data is that there are [many] patients who are staying on the treatment long-term and are able to tolerate it well. There are [numerous] patients who have this long-term data that are staying in remission off therapy, even though it has been stopped; it appears that the remissions are durable in a percentage of patients,” Julie M. Vose, MD, MBA, explained in an interview with CancerNetwork®. “This is important. It is a whole new class of drugs that have only been available for a short period of time, but these long-term data from the original clinical trials are showing us that it may have long-term benefits, even though the treatment has been stopped.”

Vose is the George and Peggy Payne Distinguished Chair of Oncology, chief of Oncology & Hematology, professor of Oncology & Hematology at the University of Nebraska Medical Center, and co-editor-in-chief of ONCOLOGY®.

EPCORE FL-1 Trial Design

The open-label trial was conducted to assess the safety and efficacy of rituximab and lenalidomide with or without epcoritamab in patients with relapsed/refractory follicular lymphoma. Patients were assigned to receive 375 mg/m² of intravenous rituximab for up to five 28-day cycles and 20 mg of oral lenalidomide for up to 12 cycles with or without subcutaneous injections of epcoritamab for up to 12 cycles.³ Epcoritamab was given at 48 mg using a step-up dosing regimen to the full dose in cycle 1.

The trial had enrolled 488 patients. Eligible patients had experienced a relapse or were refractory to at least 1 prior regimen containing an anti-CD20 monoclonal antibody with chemotherapy, were eligible to receive the study drugs, and had an ECOG performance status of 0 to 2. Those excluded included those who were refractory to lenalidomide exposure within 12 months to random assignment.

Secondary end points of the phase 3 trial included complete response rate, overall survival, minimal residual disease negativity rate, duration of response, and time to progression.

Safety Data

The combination of epcoritamab with rituximab and lenalidomide displayed a safety profile consistent with the known profiles of individual agents. Furthermore, no new safety signals were observed.

The prescribing information for epcoritamab included boxed warnings for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANs), as well as for infections and cytopenias. Moreover, serious adverse effects were observed in 51% of patients treated with epcoritamab, with serious infections occuring in 28%. Furthermore, the rate of CRS was 24% for these patients, 12% of which was deemed serious; ICANS occurred in 0.8% of patients.

The FDA previously accepted and granted priority review to a supplemental biologics license application (sBLA) for epcoritamab plus rituximab and lenalidomide in patients with follicular lymphoma after at least 1 prior line of systemic therapy in July 2025.²

The recommended regimen for the epcoritamab-based combination includes epcoritamab given subcutaneously for a maximum of twelve 28-day cycles, with lenalidomide given daily for days 1 to 21 of each cycle, and rituximab given for up to 5 cycles.

Epcoritamab dosing is recommended for a 3 step-up dosage schedule in cycle 1, at 0.16 mg on day 1, 0.8 mg on day 8, 3 mg on day 15, and 48 mg on day 22. For cycles 2 and 3, epcoritamab is recommended as a weekly 48 mg dose, before moving to a 4-week dosing of 48 mg from cycles 4 to 12.

References

1. FDA approves epcoritamab-bysp for follicular lymphoma indications. News release. FDA. November 18, 2025. Accessed November 18, 2025. https://tinyurl.com/4utb74x3
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 October 1, 2025. https://tinyurl.com/4nhj3566
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). ClincialTrials.gov. Updated July 28, 2025. Accessed October 1, 2025. https://tinyurl.com/254t76mu