Follicular Lymphoma or FL is typically an indolent, slow-growing, form of non-Hodgkin’s lymphoma (NHL) that arises from B-lymphocytes and is the second most common form of NHL accounting for approximate 20 to 30 percent of all cases being diagnosed.[1]
In the United States, about 15,000 people develop FL each year, [2] and it is considered incurable with current standard of care therapies. [3] Patients often relapse and, with each relapse the remission and time to next treatment is shorter. [4] Over time, transformation to diffuse large B-cell lymphoma (DLBCL), an aggressive form of NHL associated with poor survival outcomes, can occur in more than 25 percent of FL patients. [5]
Although there is currently no standard treatment for FL, over the past decade, chemotherapy platforms have changed, with bendamustine + rituximab becoming a commonly frontline strategy.
However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, the development of novel combinations therapies, and strategies to reduce the risk of transformation. To help in this, multitude clinical studies are evaluating the possible benefits of novel therapies in both the frontline and relapsed/refractory settings. [6]
Among the novel treatment options being evaluated in clinical studies is epcoritamab, a bispecific antibody being developed by Genmab, in combination with rituximab and lenalidomide (R2).
Epcoritamab (approved under the brand name EPKINLY® in the U.S. and Japan, and TEPKINLY® in the EU), is an IgG1-bispecific antibody created using Genmab’s proprietary DuoBody® technology and administered subcutaneously. Genmab’s DuoBody-CD3 technology is designed to direct cytotoxic T cells selectively to elicit an immune response toward target cell types. Epcoritamab is designed to simultaneously bind to CD3 on T cells and CD20 on B cells and induces T-cell-mediated killing of CD20+ cells. [7]
Phase 3 EPCORE® FL-1 study
The EPCORE FL-1 study (NCT05409066) is a Phase 3 open-label interventional clinical trial designed to evaluate the safety and efficacy of epcoritamab plus rituximab and lenalidomide (R2) versus R2 alone in patients with relapsed/refractory (R/R) follicular lymphoma (FL). The dual primary endpoints are ORR and PFS assessed by independent review committee (IRC) per Lugano criteria.
The study met its dual primary endpoints of overall response rate (ORR; 95.7%, p < 0.0001) and progression-free survival (PFS, HR 0.21, p-value <0.0001), demonstrating statistically significant and clinically meaningful differences in both endpoints, reducing the risk of disease progression or death by 79%. The results, derived from a pre-planned interim analysis, will be submitted for presentation at the 67th Annual Meeting and Exposition of the American Society of Hematology (ASH) and will serve as the basis for global regulatory submissions.
Supplemental Biologics License Application
Separately, on July 24, the U.S. Food and Drug Administration (FDA) accepted for priority review the supplemental Biologics License Application (sBLA) for epcoritamab plus R2 following at least one prior systemic therapy.
Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. Photo courtesy © 2018 – 2025. Used with permission.The sBLA submission was based on data from a first interim analysis that demonstrated statistically significant improvements in ORR (95.7%, p-value < 0.0001) and PFS (HR 0.21, p-value <0.0001, based on the intent-to-treat population). Under the Prescription Drug User Fee Act (PDUFA), the FDA has set a target action date of November 30, 2025. If approved, epcoritamab plus R2 would be the first bispecific antibody combination regimen available in the U.S. as a second-line treatment option for patients with R/R FL.
“While therapeutic options exist for patients with relapsed or 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,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.
“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.”
Safety profile
The safety profile of epcoritamab in combination with R2 in adult patients with R/R FL was consistent with the known safety profiles of the individual regimens (epcoritamab and R2) and as presented in the U.S. prescribing information for epcoritamab. No new safety signals were observed.
The U.S. FDA has granted accelerated approval of single agent epcoritamab for the treatment of adults with R/R FL after two or more lines of systemic therapy. The U.S. FDA also granted Breakthrough Therapy Designation (BTD) to epcoritamab in combination with R2 for the treatment of adult patients with R/R FL who have received at least one prior line of therapy. The safety and efficacy of epcoritamab in combination with R2 in R/R FL is currently being evaluated in clinical trials and is not approved or established in the U.S., EU or in any other territory.
Clinical trials
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 ID NCT05409066
A Phase 3 Trial of Epcoritamab vs Investigator’s Choice Chemotherapy in Relapsed/Refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL) (EPCORE DLBCL-1)
ClinicalTrials.gov ID NCT04628494
A Study to Evaluate Change in Disease Activity of Subcutaneous (SC) Epcoritamab Combined With Intravenous and Oral Rituximab, Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine, and Prednisone (R-CHOP) or R-CHOP in Adult Participants With Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) (EPCORE DLBCL-2) – ClinicalTrials.gov ID NCT05578976
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 Previously Untreated Follicular Lymphoma (EPCORE™FL-2) – ClinicalTrials.gov ID NCT06191744
A Study of Subcutaneously Injected Epcoritamab Plus Oral Lenalidomide Tablets Compared to Intravenously (IV) Infused Rituximab Plus IV Infused Gemcitabine and IV Infused Oxaliplatin in Adult Participants With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (EPCORE DLBCL-4) – ClinicalTrials.gov ID NCT06508658
Highlights of Prescribing Information
Epcoritamab (EPKINLY®; Genmab and AbbVie) [Prescribing Information]
Rituximab (Retuxan®; Genentech and Biogen) [Prescribing Information]
Lenalidomide (Revlimid®; Bristol-Myers Squibb Company.[Prescribing Information]
Bendamustine (Bendeka®; Teva)[Prescribing information]
References
[1]Lymphoma Research Foundation Online. Last accessed in July 2025
[2] Leukemia & Lymphoma Society. Online Last accessed in July 2025
[3] Ghione P, Palomba ML, Ghesquieres H, et al. Treatment patterns and outcomes in relapsed/refractory follicular lymphoma: results from the international SCHOLAR-5 study. Haematologica. 2023;108(3):822-832. doi: 10.3324/haematol.2022.281421.
[4] Rivas-Delgado A, Magnano L, Moreno-Velázquez M, et al. Response duration and survival shorten after each relapse in patients with follicular lymphoma treated in the rituximab era. Br J Haematol. 2018;184(5):753-759. doi:10.1111/bjh.15708.
[5] Al-Tourah AJ, Gill KK, Chhanabhai M, et al. Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol. 2008 Nov 10;26(32):5165-9. doi: 10.1200/JCO.2008.16.0283. Epub 2008 Oct 6. PMID: 18838711.
[6] Kahl B. High-risk follicular lymphoma: Treatment options. Hematol Oncol. 2021 Jun;39 Suppl 1:94-99. doi: 10.1002/hon.2853. PMID: 34105813.
[7] Engelberts PJ, et al. DuoBody-CD3xCD20 Induces Potent T-Cell-Mediated Killing of Malignant B Cells in Preclinical Models and Provides Opportunities for Subcutaneous Dosing. EBioMedicine. 2020;52:102625. doi: 10.1016/j.ebiom.2019.102625.
Featured image courtesy © 2019 – 2025 Fotolia/Adobe. Used with permission
DOI
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