Adding epcoritamab to standard second-line therapy improves follicular lymphoma outcomes

(Press-News.org) (ORLANDO, Dec. 7, 2025) In a new trial, patients with follicular lymphoma had a significantly higher response to treatment and a nearly 80% reduction in the risk of death or disease progression if they received epcoritamab in addition to the standard second-line regimen versus the standard regimen alone. The study is the first reported randomized controlled trial to test a bispecific antibody combination in follicular lymphoma and suggests the combination could offer an effective alternative to chemotherapy that can be safely administered on an outpatient basis.

Based on the study results, the U.S. Food and Drug Administration (FDA) approved epcoritamab with rituximab and lenalidomide for relapsed or refractory follicular lymphoma in November 2025.

“The addition of epcoritamab to rituximab and lenalidomide very substantially increased the response rates, depth of response, and duration of benefit and therefore may represent a new standard of care in patients with follicular lymphoma,” said lead study author Lorenzo Falchi, MD, assistant attending physician in the lymphoma service at Memorial Sloan Kettering Cancer Center in New York. “We are at a point in time when chemo-free approaches based on immunotherapy can seriously challenge chemotherapy as the standard of care. We will not know for a long time if [this regimen] is curative, but it’s certainly the beginning of a bright era for chemo-free therapy for follicular lymphoma.”

Follicular lymphoma is a slow-growing non-Hodgkin lymphoma that can progress to a more aggressive form. Patients who see their cancer return after an initial round of treatment have limited options and often experience subsequent relapses.

The immunotherapeutic combination rituximab and lenalidomide (known as R2) has become a standard second-line treatment for follicular lymphoma, while epcoritamab, a bispecific antibody, was more recently approved for follicular lymphoma that is relapsed or refractory (R/R) after two or more lines of systemic therapy. R2 and epcoritamab operate through different mechanisms to enhance the ability of a patient’s immune system to recognize and eradicate cancer cells.

The study randomized 488 patients with R/R follicular lymphoma to receive epcoritamab plus R2 or R2 alone for up to 12 cycles. At a median follow-up of just under 15 months, the group receiving epcoritamab plus R2 showed a significantly higher overall response rate (95.1% versus 79.2% among the control group) and a significantly longer progression-free survival (85.5% versus 40.2% at 16 months), meeting both of the trial’s primary endpoints.

Epcoritamab plus R2 also outperformed R2 alone for the trial’s secondary endpoints, with 82.7% of patients in this arm seeing a complete response (CR) to treatment versus 49.8% among those who received R2 alone. Participants who received epcoritamab plus R2 also showed a significantly longer duration of response and CR. The results were consistent across all subgroups analyzed.

Additionally, researchers noted that very few patients who received epcoritamab required subsequent treatments during the study period, suggesting that the new regimen can help patients avoid or delay further treatments and their associated toxicities. At 16 months, 92.8% of patients in this group remained free from new anti-lymphoma treatments, compared with 64.9% among those who received R2 alone.

“A time-limited therapy that is not followed by another therapy for a long time is certainly a very good value for patients,” said Dr. Falchi.

Participants who received epcoritamab plus R2 experienced a higher rate of adverse events, with grade 3 or 4 treatment-related adverse events occurring in 90.1% of patients receiving epcoritamab and 67.6% of patients in the control group. This increase was driven largely by a higher rate of low white blood cell counts and infections among those receiving epcoritamab. There was no evidence of neurological toxicity and no reports of grade 3 or 4 cytokine release syndrome (CRS). According to researchers, this suggests that the combined regimen is safe to administer in a variety of medical settings.

“There has been some hesitancy to use bispecific antibodies in a community setting because of CRS,” said Dr. Falchi. “The prospect of a subcutaneous, completely outpatient treatment that does not result in a significant rate of CRS is good news for giving more patients the best opportunity for a response.”

The study also tested two different step-up dosing regimens for the epcoritamab–R2 combination, showing that three initial smaller doses resulted in a reduced rate of low-grade CRS compared with a course of just two initial smaller doses.

Given the study’s relatively short median follow-up time to date, the researchers will continue to track participants to assess longer-term outcomes. In addition, a separate study is underway to test the epcoritamab–R2 combination in a frontline setting. Dr. Falchi added that epcoritamab could also be investigated as a single-agent treatment for patients who are not candidates for R2.

The study was funded by Genmab and AbbVie Inc. The results were simultaneously published in the Lancet.

Lorenzo Falchi, MD, of Memorial Sloan Kettering Cancer Center, will present this study on Sunday, December 7, 2025, at 10:15 a.m. Eastern time in West Hall D2 of the Orange County Convention Center.

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