Epcoritamab Plus Rituximab and Lenalidomide Hits Both Primary End Points in R/R Follicular Lymphoma

The combination of epcoritamab-bysp (Epkinly), rituximab (Rituxan), and lenalidomide (Revlimid) demonstrated significant improvements in overall response rate (ORR) and progression-free survival (PFS) compared with rituximab and lenalidomide in patients with relapsed/refractory follicular lymphoma, meeting the coprimary end points of the phase 3 EPCORE FL-1 (NCT05409066).¹

Data from a preplanned interim analysis of EPCORE FL-1 revealed that patients who received the triplet experienced a 79% reduction in the risk of death or disease progression compared with those treated with only rituximab and lenalidomide (HR, 0.21; P < .0001). Moreover, there was a significant benefit in terms of ORR in favor of the investigational arm (P <.0001).

In July 2025, the FDA accepted the supplemental Biologics License Application (sBLA) of epcoritamab plus rituximab and lenalidomide for the treatment of patients with relapsed/refractory follicular lymphoma following at least 1 prior systemic therapy. The sBLA submission was based on prior findings from EPCORE FL-1. The FDA set a Prescription Drug User Fee Act target action date of November 30, 2025.

“[Although] therapeutic options exist for patients with relapsed/refractory follicular lymphoma, response rates tend to decline and durability diminishes with each subsequent line of treatment, which can increase the risk of the disease transforming into aggressive large-cell lymphoma,” Jan van de Winkel, PhD, president and chief executive officer of Genmab, said in a news release. “The results from this trial, and the decision from the FDA to accept the sBLA for priority review, demonstrate the potential of this epcoritamab combination therapy to reshape the treatment landscape and reinforces our shared commitment with AbbVie to advance epcoritamab as a potential core therapy across B-cell malignancies.”

EPCORE FL-1 was an open-label study that evaluated epcoritamab plus rituximab and lenalidomide in adult patients with relapsed/refractory follicular lymphoma who received at least 1 prior systemic regimen containing an anti-CD20 monoclonal antibody plus chemotherapy.² Additional inclusion criteria consisted of having an estimated creatine clearance of at least 50 mL/minute, at least 1 measurable lesion per CT scan or MRI, and an ECOG performance status of 0 to 2. Patients were also required to have stage II to IV disease without evidence of histologic transformation to an aggressive lymphoma and CD20-positive disease.

Eligible patients were randomly assigned 1:1 to receive subcutaneous epcoritamab at 48 mg for up to twelve 28-day cycles in combination with intravenous rituximab and oral lenalidomide or rituximab and lenalidomide alone.^2,3 Patients in both arms received rituximab at 375 mg/m² for up to 5 cycles and lenalidomide at 20 mg for up to 12 cycles.²

The coprimary end points were best overall response (BOR) rate and PFS. Secondary end points included complete response (CR) rate, overall survival, minimal residual disease negativity rate, change in Functional Assessment of Cancer Therapy–Lymphoma scale, investigator-assessed PFS, investigator-assessed BOR rate, investigator-assessed CR rate, duration of CR, time to disease progression, and event-free survival.

In terms of safety, findings from the interim analysis showed that the safety profile of epcoritamab plus rituximab and lenalidomide in patients with relapsed/refractory follicular lymphoma was consistent with the known safety profiles of the individual regimens.¹ Notably, no new safety signals were reported.

In June 2024, the FDA approved epcoritamab monotherapy for the treatment of patients with relapsed/refractory follicular lymphoma after at least 2 lines of systemic therapy.⁴ The approval was supported by findings from the phase 1/2 EPCORE NHL-1 trial (GCT3013-01; NCT03625037), which demonstrated that patients who received the agent (n = 127) achieved an ORR of 82% (95% CI, 74.1%-88.2%).

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

Additional data from the interim analysis of EPCORE FL-1 will be submitted for presentation at the 2025 ASH Annual Meeting and Exposition in December, according to Genmab.The findings will also serve as the basis for global regulatory submissions.

References

1. 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
2. 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 August 7, 2025. https://clinicaltrials.gov/study/NCT05409066
3. 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
4. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. FDA. June 26, 2024. Accessed August 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-follicular-lymphoma