On November 18, 2025, the U.S. Food and Drug Administration (FDA) approved the triplet epcoritamab plus lenalidomide and rituximab (R2) for patients with relapsed or refractory follicular lymphoma, based on groundbreaking results from the phase 3 EPCORE FL-1 Trial (NCT05409066). (1)
MSK lymphoma specialist Lorenzo Falchi, MD, presented the latest results for the study on Sunday, December 7, 2025 at the American Society of Hematology’s 67th Annual Meeting and Exposition in Orlando, Florida. The study was featured in the ASH 2025 Press Program, and Dr. Falchi was the lead author of the paper published simultaneously in The Lancet. (2)
Epcoritamab plus R2 resulted in substantial increases in the objective response rate (ORR) and progression-free survival (PFS) compared to R2 alone, the co-primary endpoints of the trial. The triplet combination also outperformed the standard-of-care on the secondary endpoints of complete response rate (CR) and duration of response.
“EPCORE FL-1 is the first randomized controlled trial of a chemotherapy-free bispecific combination in follicular lymphoma,” said Dr. Falchi. “The combination of epcoritamab plus R2 achieved some of the highest complete response rates ever observed in patients with advanced follicular lymphoma.”
Current Therapies for Advanced Follicular Lymphoma
Follicular lymphoma, the second most common lymphoma, is a chronic, indolent disease that is considered incurable. Most patients respond well to first-line treatment, but as the cancer relapses, responses are less likely and become shorter-lived with each subsequent line.
Lenalidomide produces cytotoxic and immunomodulatory effects. It works by binding to the cereblon protein and tagging the substrate proteins aiolos, lkaros, and casein kinase 1alpha for degradation. Rituximab is an antibody that binds to the CD20 antigen on normal pre-B and mature B lymphocytes, triggering an immune response against CD20-positive cells. The U.S. Food and Drug Administration (FDA) approved R2 for previously treated follicular lymphoma in May 2019.
“R2 is an internationally accepted standard-of-care as a treatment for follicular lymphoma in the second line and beyond,” said Dr. Falchi. “However, it is certainly not a panacea as complete response rates do not exceed 50%, and most patients experience disease progression within a few years of therapy, as we saw in the AUGMENT trial (NCT01938001) that helped to establish R2 as the standard.”
Epcoritamab is a bispecific T-cell engager that binds to CD20 on cancerous B cells and CD3 on healthy T cells. The FDA granted accelerated approval to epcoritamab monotherapy for treating patients with relapsed or refractory follicular lymphoma in June 2024 and traditional approval on November 18, 2025. (1)
The approval was based on safety and efficacy data from the EPCORE NHL-1 trial (NCT03625037), an open-label, multicenter, single-arm trial that enrolled multiple cohorts of patients with relapsed or refractory follicular lymphoma after at least two lines of systemic therapy. Several treatment arms included combinations with epcoritamab.
MSK has led arm 2 of the EPCORE NHL-2 trial since phase 1, testing the safety and efficacy of epcoritamab plus rituximab and lenalidomide (R2) in patients with recurrent follicular lymphoma. The most recent results from phase 1b/2 (NCT04663347), published online in Blood ([iii]) in September 2025, showed that the cohort treated with fixed-duration epcoritamab plus R2 achieved deep, durable responses with manageable safety and favorable outcomes, regardless of risk features.
The ORR was 96% and the CR was 88%. CR rates were 90% for patients with primary refractory lymphoma, 82% for those refractory to anti-CD20 and chemotherapy, and 83% for patients with disease progression within 24 months of first-line treatment. (2)
The two-year estimates for remaining in CR, overall survival (OS), and not starting another anti-lymphoma therapy were 82%, 90%, and 84%, respectively. Common treatment-related adverse events included neutropenia (65%), COVID-19 (59%), and cytokine release syndrome (CRS) (51%). (2)
EPCORE FL-1 Design
The phase 3 EPCORE FL-1 trial is taking place at 273 international study sites, including MSK. The trial is active but no longer recruiting.
Participants were randomly assigned to receive epcoritamab plus R2 or R2 alone over 12 cycles, each 28 days in duration. The trial employed a step-up dosing protocol for patients in the epcoritamab cohort based on data from EPCORE NHL-2, aiming to minimize CRS events.
EPCORE FL-1 Results
The present analysis included 488 patients. Results from the first 16 months of follow-up met both of the trial’s primary endpoints as follows: (1)
- ORR was 95.1% for epcoritamab plus R2 versus 79.2% for R2 alone (p < 0.0001).
- PFS was superior in the experimental arm, with a hazard ratio of 0.21 (p < 0.0001). The PFS rates were 85.5% versus 40.2%, respectively.
“The PFS benefit was preserved across all pre-specified patient groups, including age, sex, country, number of prior treatments, bulky disease, progression of disease within 24 months, and having double-refractory disease,” Dr. Falchi noted.
Epcoritamab plus R2 also outperformed R2 alone on key secondary endpoints:
- CR was 79.2% versus 49.8%, respectively
- Patients who received epcoritamab plus R2 experienced a significantly longer duration of response and CR across all subgroups.
The safety data were in line with known profiles for epcoritamab and R2, with no unexpected adverse events. Grade 3 and higher adverse events were somewhat higher in the experimental arm, primarily neutropenias and infections, but all were manageable. CRS occurred in 35% of patients receiving epcoritamab, but there were no grade 3 or 4 CRS events. No neurological toxicities were observed. (1)
“The current recommended protocol for epcoritamab alone is hospital admission for the third dose on cycle 1, day 15,” said Dr. Falchi. “The step-up dose design in EPCORE FL-1 led to fewer CRS events overall. The low CRS risk is especially notable as epcoritamab plus R2 was given on a fully outpatient basis, which may help overcome hesitancy to use bispecific antibodies in community settings.”
Notably, among patients who received the triplet, only a handful have required additional treatment as of 15 months. “PFS is important, but treatment-free survival also has a big value for patients,” Dr. Falchi said. “So far, most patients treated with epcoritamab plus R2 have achieved disease remission without needing further treatments, which are often associated with side effects, and the need for clinic visits and tests,” said Dr. Falchi.
Key Takeaways
“The EPCORE FL-1 trial results are excellent news for patients,” said Dr. Falchi. “The data suggests that most patients who are candidates for R2, should be considered for epcoritamab plus R2 instead.”
“We will continue to follow patients to see if the EPCORE FL-1 results are preserved beyond 15 months of follow-up,” Dr. Falchi said. “Whether epcoritamab plus R2 is curative, the “holy grail” of follicular lymphoma research, will not be known for a long time, but we’ve certainly entered a bright new era in favor of bispecific antibody combinations challenging standard-of-care chemotherapy.”
The study was sponsored by Genmab in collaboration with AbbVie Inc. Access disclosures for Dr. Falchi. Learn more about MSK clinical trials for patients with follicular lymphoma.