When epcoritamab was added to lenalidomide and rituximab, response rates were significantly higher and progression-free survival was prolonged for patients with follicular lymphoma treated in the second-line setting or beyond, according to findings from the phase III EPCORE FL-1 trial presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 466). Trial results were also simultaneously published in The Lancet.
“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 [chemotherapy-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 [chemotherapy-free] therapy for follicular lymphoma.”
Background and Study Methods
The combination of epcoritamab, a bispecific CD20-directed CD3 T-cell engager, plus lenalidomide and rituximab demonstrated promise as a chemotherapy-free regimen for patients with follicular lymphoma in the second-line setting in the phase Ib/II EPCORE NHL-2 trial, with a 97% overall response rate and manageable safety.
EPCORE FL-1 is the first global phase III trial of a fixed-duration regimen of a bispecific antibody with lenalidomide and rituximab in patients with CD20-positive relapsed or refractory follicular lymphoma being treated in the second-line setting or beyond. Patients who were eligible by GELF criteria (n = 488) were randomly assigned to receive lenalidomide and rituximab with or without added epcoritamab for up to 12 cycles. Epcoritamab was administered subcutaneously with a 2-step-up dose or 3-step-up dose regimen and full doses afterwards at a weekly schedule for the first three cycles and every 28 days thereafter.
Key Findings
A preplanned interim analysis in the first 232 patients to be followed for at least a year showed an objective response rate of 95.7% (95% confidence interval [CI] = 90.2%–98.6%) in the epcoritamab plus lenalidomide and rituximab arm in comparison with 81.0% in the lenalidomide and rituximab arm (95% CI = 72.7%–87.7%; P < .0001). At 1 year, the duration of response rate was 91.4% (95% CI = 84.0%–95.4%) in the epcoritamab plus lenalidomide and rituximab arm vs 57.0% (95% CI = 44.2%–68.0%) in the lenalidomide and rituximab arm.
In the intention-to-treat population, progression-free survival was significantly prolonged in patients treated with the triplet regimen than those treated with the doublet regimen (hazard ratio [HR] = 0.21; 95% CI = 0.13–0.33; P < .0001). Clinical complete response rates were 74.5% (95% CI = 68.5%–79.8%) and 43.3% (95% CI = 37.0%–49.7%; P < .0001) in the arms with and without epcoritamab, respectively.
With the 3-step-up dose of epcoritamab (n = 131), rates of cytokine-release syndrome were low grade and occurred in just under one-fourth of patients, mostly at the time of the first 48-mg full dose of epcoritamab, and all resolved. “There has been some hesitancy to use bispecific antibodies in a community setting because of cytokine-release syndrome,” said Dr. Falchi. “The prospect of a subcutaneous, completely outpatient treatment that does not result in a significant rate of cytokine-release syndrome is good news for giving more patients the best opportunity for a response.” The overall rate of grade 1/2 cytokine-release syndrome among patients who received epcoritamab was 26%.
One case of grade 1 immune effector cell–associated neurotoxicity syndrome was reported in the triplet arm, which resolved.
Grade 3/4 treatment-emergent adverse events were observed in 88.1% of patients in the triplet arm and in 62.2% in the doublet arm, including higher rates of neutropenia and infections. Febrile neutropenia of grade 3 or 4 was reported in 6.2% of patients treated with epcoritamab and in 2.1% of patients not treated with epcoritamab. Fatal events occurred in 0.8% of patients in the added-epcoritamab arm vs in 2.9% in the arm without epcoritamab, and none were considered related to treatment with epcoritamab.
Treatment-emergent adverse events led to discontinuation in 16% of patients treated in the triplet arm vs in 11.8% in the doublet arm.
Disclosure: The study was funded by Genmab and AbbVie Inc. For full disclosures of the study authors, visit hematology.org.
