Epcoritamab Plus Lenalidomide Significantly Improves PFS in Relapsed/Refractory DLBCL

A fixed-duration combination of epcoritamab-bysp (Epkinly; Genmab, AbbVie) and lenalidomide (Revlimid; Celgene Corporation) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with rituximab (Rituxan; Genentech), gemcitabine (Gemzar; Eli Lilly), and oxaliplatin (R-GemOx, Eloxatin; Sanofi-Aventis) in adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), according to topline findings from the phase 3 EPCORE DLBCL-4 trial (NCT06508658).¹

Epcoritamab plus lenalidomide reduced the risk of disease progression or death by approximately 60% under US censoring rules and by 56% under censoring rules used outside the United States compared with R-GemOx.¹ These findings support the potential use of the chemotherapy-free epcoritamab-based regimen earlier in the R/R DLBCL treatment pathway, although complete efficacy and safety results have not yet been presented or published.

Addressing an Ongoing Need in R/R DLBCL

DLBCL is an aggressive B-cell malignancy and the most common form of non-Hodgkin lymphoma, representing approximately 25% to 30% of all non-Hodgkin lymphoma cases worldwide. Although frontline immunochemotherapy may produce durable remissions, a significant number of patients experience disease that relapses or does not respond adequately to initial treatment.²

Treatment selection after relapse is guided by the timing of disease progression, prior therapies, eligibility for autologous stem cell transplantation (ASCT) or chimeric antigen receptor (CAR) T-cell therapy, comorbidities, and the patient’s ability to tolerate additional chemotherapy. Patients who are unable to undergo transplantation or receive CAR T-cell therapy may require effective and more accessible alternatives.

Epcoritamab is a subcutaneously administered IgG1-bispecific antibody that simultaneously binds CD3 on T cells and CD20 on malignant B cells, redirecting and activating T cells to eliminate CD20-positive cells.³

In 2023, the FDA granted accelerated approval to epcoritamab as a monotherapy for adults with R/R DLBCL not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma following at least 2 lines of systemic therapy. The approval was based on findings from EPCORE NHL-1, in which the overall response rate was 61% and the complete response rate was 38%.³ Longer-term findings subsequently demonstrated an overall response rate of approximately 63.1% and complete response rate of 40.1% after a median follow-up of about 25.1 months.⁴

Lenalidomide is an oral immunomodulatory therapy with multiple antineoplastic effects, including immune-cell activation and disruption of signaling that supports malignant cell survival. Combining lenalidomide with a T-cell–engaging bispecific antibody may augment immune activity against lymphoma cells while avoiding conventional cytotoxic chemotherapy.

EPCORE DLBCL-4 Demonstrates PFS Benefit

EPCORE DLBCL-4 is a global, randomized, open-label, multicenter phase 3 trial evaluating fixed-duration subcutaneous epcoritamab plus lenalidomide against R-GemOx in adults with R/R large B-cell lymphoma. Eligible patients received at least 1 previous systemic treatment that included an anti-CD20 monoclonal antibody-containing chemotherapy regimen.^1,5

Patients had experienced disease relapse or treatment failure and were either not candidates for ASCT or were either ineligible for or unable to receive CAR T-cell therapy. The study population included patients with DLBCL not otherwise specified, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, grade 3B follicular lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, and Epstein-Barr virus–positive DLBCL.¹

The trial met its primary PFS end point. Under censoring rules used for the US analysis, epcoritamab plus lenalidomide reduced the risk of progression or death by 60% compared with R-GemOx (HR, 0.40; 95% CI, 0.30-0.55; P < .0001). Using censoring rules applied outside the US, the risk was reduced by 56% (HR, 0.44; 95% CI, 0.33-0.60; P < .0001).¹

The reported safety profile of the combination was consistent with the previously characterized profiles of epcoritamab and lenalidomide individually. However, Genmab did not disclose detailed rates of adverse events, treatment discontinuations, cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), infections, cytopenias, response rates, overall survival (OS), or median PFS in the topline announcement. These data are expected to be submitted for presentation at a future medical meeting.¹

Implications for Practice

If supported by the complete trial findings and ultimately authorized by regulatory agencies, fixed-duration epcoritamab plus lenalidomide may provide a nonchemotherapy alternative for patients with R/R DLBCL who cannot proceed to transplantation or CAR T-cell therapy. Its subcutaneous and oral components may also affect treatment administration, resource use, and patient preferences compared with an intravenous chemoimmunotherapy regimen.

Epcoritamab carries boxed warnings for CRS and ICANS, as well as warnings for serious infections and cytopenias.³ Health care professionals should also consider lenalidomide-associated risks—including myelosuppression, thromboembolism, and embryo-fetal toxicity—along with applicable prescribing and dispensing requirements.

Until complete EPCORE DLBCL-4 findings are available, the magnitude and durability of response, comparative safety, effects on quality of life, and OS benefit remain important unanswered considerations. Genmab and AbbVie stated that they plan to discuss the findings with global regulatory authorities.¹

REFERENCES

1. Genmab announces positive phase 3 results for epcoritamab plus lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma, demonstrating statistically significant improvement in progression-free survival. Genmab. News release. June 29, 2026. Accessed June 30, 2026. https://ir.genmab.com/news-releases/news-release-details/genmab-announces-positive-phase-3-results-epcoritamab-plus

2. Sehn LH, Salles G. Diffuse Large B-Cell Lymphoma. N Engl J Med. 2021;384(9):842-858. doi:10.1056/NEJMra2027612

3. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. FDA. News release. May 19, 2023. Accessed June 30, 2026. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-diffuse-large-b-cell

4. Thieblemont C, Karimi YH, Ghesquieres H, et al. Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial. Leukemia. 2024;38(12):2653-2662. doi:10.1038/s41375-024-02410-8

5. A study of subcutaneously injected epcoritamab with lenalidomide compared to rituximab, gemcitabine, and oxaliplatin in adults with relapsed or refractory diffuse large B-cell lymphoma (EPCORE DLBCL-4). ClinicalTrials.gov identifier: NCT06508658. Updated June 26, 2026. Accessed June 30, 2026. https://clinicaltrials.gov/study/NCT06508658