Among patients with relapsed/refractory follicular lymphoma, fixed-duration Epkinly (epcoritamab) plus Rituxan (rituximab) and Revlimid (lenalidomide; R2) was associated with significant improvements in progression-free survival (PFS) and response rates compared with R2 alone.
Findings from the phase 3 EPCORE FL-1 trial were presented in a press briefing during the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.
At a median follow-up of 14.8 months, results showed that the median PFS per independent review committee (IRC) was not estimable with Epkinly plus R2 compared with 11.7 months with R2 alone, leading to a 79% reduction in the risk of disease progression or death. The concordance rate was 94% for PFS between IRC and investigator assessment. The estimated 16-month PFS rates were 85.5% and 40.2%, respectively.
Glossary
Progression-Free Survival (PFS): The length of time during and after treatment that the cancer does not grow or get worse.
Objective Response Rate (ORR): The percentage of patients whose cancer shrinks or disappears with treatment. It includes both complete and partial responses.
Complete Response (CR) Rate: The percentage of patients whose cancer completely disappears on tests after treatment.
Partial Response (PR) Rate: The percentage of patients whose cancer shrinks significantly—but does not disappear entirely—after treatment.
Stable Disease (SD): When the cancer does not shrink enough to be called a response but also does not grow or spread. It remains “stable.”
Progressive Disease (PD): When the cancer grows or spreads despite treatment.
Overall Survival (OS): How long patients stay alive after diagnosis or the start of treatment, no matter what happens with the cancer.
Neutropenia: A low number of neutrophils, an important white blood cell that fights infection. Neutropenia increases the risk of infections and is a common side effect of some treatments.
Cytokine Release Syndrome (CRS): A reaction that can happen when certain treatments activate the immune system very strongly. It can cause fever, tiredness, and low blood pressure. Doctors monitor and treat CRS carefully.
Thrombocytopenia: A low number of platelets, the blood cells that help stop bleeding. This can lead to easy bruising, nosebleeds, or bleeding that takes longer to stop.
Pyrexia: The medical word for fever—when the body temperature is higher than normal.
Febrile Neutropenia: A combination of fever and neutropenia (low infection-fighting white cells). This is treated as an emergency because the body may not be able to fight infections well.
The Epkinly regimen elicited a 95% objective response rate (ORR) compared with 79% with R2 alone. In the Epkinly arm, the complete response (CR) rate was 83% and the partial response (PR) rate was 12%; one patient had stable disease (SD), 3% of patients had progressive disease (PD) and 2% were not evaluable. In the R2 arm, the CR rate was 50% and the PR rate was 29%; 7% of patients each had SD, PD and were not evaluable.
“[Epkinly] and R2 is a novel chemotherapy-free, fixed-duration therapy that is suitable for outpatient administration, and we believe sets a new benchmark as standard of care for second-line [and beyond] follicular lymphoma,” lead study author Dr. Lorenzo Falchi of the Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York said in the oral presentation. “We’re happy to see that the FDA granted full approval to [Epkinly] and R2 on Nov. 18, 2025, for [this patient population].”
R2 is the only second-line alternative to chemoimmunotherapy-based treatment for patients with relapsed/refractory follicular lymphoma. The FDA initially approved Epkinly, a CD3xCD20 bispecific antibody, as a single agent for the treatment of patients with relapsed/refractory follicular lymphoma following at least two lines of systemic therapy.
Early data from the phase 1b/2 EPCORE NHL-2 trial, which evaluated fixed-duration Epkinly plus R2 for relapsed/refractory follicular lymphoma, demonstrated deep and durable responses and a manageable safety profile.
In November 2025, the FDA also approved Epkinly in combination with R2 in relapsed/refractory follicular lymphoma, based on the phase 3 EPCORE FL-1 findings, which is what Falchi presented during the press briefing. In the international, open-label, EPCORE FL-1 trial, patients underwent randomization to receive fixed-duration Epkinly at 48 milligrams (mg) plus R2 (243 patients) or R2 alone (245 patients).
Epkinly was administered in a three-step-up, two-dosing schedule at 0.16 mg on day 1, 0.8 mg on day 8 and 3 mg on day 15, all in cycle 1. Cycles 2 and 3 were administered weekly, and cycles 4 to 12 were administered every four weeks. Rituxan was given at 375 mg/m2 for five cycles; the agent was given weekly in cycle 1 and every 4 weeks in cycles 2 through 5. Lastly, Revlimid was given at 20 mg for 12 cycles; treatment was given daily in cycles 1 through 12 on days 1 through 21.
The data cutoff date was May 24, 2025, and patients were enrolled between October 2022 and January 2025.
Baseline characteristics showed that the median age was 61 years and 40% of patients were at least 65 years old; 57% of patients were male and 72% were White. Thirty-one percent of patients had an ECOG performance status of 1 to 2, while 83% had Ann Arbor stage 3 to 4 disease. Regarding Follicular Lymphoma International Prognostic Index, the breakdown of scores was 0 to 1 (24%), 2 (32%) and 3 to 5 (44%). Twenty-two percent of patients had bulky disease, consisting of at least 7 cm.
The median time from initial diagnosis to randomization was five years, and the median number of prior lines of therapy was one, with most patients receiving one (59%), two (24%) or at least three (17%). All patients received a prior anti-CD20 antibody and 3% had received prior R2. Forty-one percent of patients experienced disease progression within two years from starting frontline therapy; 34% of patients were refractory to their first-line therapy, and 37% of patients had double-refractory disease.
Additional efficacy data showed that the median DOR with Epkinly plus R2 was NE compared with 11.5 months with R2 alone.
The Epkinly regimen also extended time to next lymphoma treatment (TTNLT); the median was NE (NE-NE) compared with 24.3 months with R2 alone. At 16 months, 92.8% of patients on Epkinly plus R2 remained free from new anti-lymphoma therapy versus 64.9% of those on R2 alone.
Falchi noted there is a positive trend for OS with the Epkinly arm, which is NE in both arms, adding that there are 10 and 25 events in the Epkinly and R2-alone arms, respectively. Sixteen-month estimates for OS were 95.8% for Epkinly plus R2 versus 88.8% with R2 alone.
Regarding safety, any-grade side effects occurred in 100% and 99% of patients on Epkinly plus R2 and R2 alone, with grade 3 (severe) or higher side effects at 90% and 68%, respectively. Serious side effects occurred in 56% and 29%, respectively, and side effects that led to treatment discontinuation occurred in 19% and 12% of patients.
Any-grade and grade 3 or higher side effects of clinical interest occurring in at least 20% of patients on Epkinly/R2 and R2 alone included infections (77% and 33% versus 53% and 16%), neutropenia (74% and 69% versus 52% and 42%), cytokine release syndrome (any-grade, 35% versus <1%) thrombocytopenia (28% and 9% versus 18% and 6%), pyrexia (24% and <1%; 14% and 1%), rash (24% and 8% versus 22% and 4%) and COVID-19 (22% and 3% vs 13% and 2%).
On the Epkinly arm, 3% of patients discontinued due to neutropenia versus 2% in the R2-alone arm. Febrile neutropenia occurred in 6% and 3% of patients, respectively. Discontinuation rates due to infections occurred in 6% and 1% of patients, respectively.
Two percent and 4% of patients on Epkinly and R2 and R2 alone experienced fatal side effects. “Despite these higher rates of [side effects] in the Epkinly and R2 arm, the median relative dose intensity was greater than 90%,” Falchi added.
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References
- “Primary phase 3 results from the EPCORE- FL-1 trial of epcoritamab with rituximab and lenalidomide (R2) versus R2 for relapsed or refractory follicular lymphoma” by Dr. Lorenzo Falchi et al., Blood.
- “Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed/refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial,” by Dr. Lorenzo Falchi et al., Lancet.
- “EPKINLY™ (epcoritamab-bysp) injection prescribing information,” FDA; https://tinyurl.com/mrvfmaur
- “Fixed-duration epcoritamab plus R2 drives favorable outcomes in relapsed or refractory follicular lymphoma” by Dr. Lorenzo Falchi et al., Blood.
- “FDA approves epcoritamab-bysp for follicular lymphoma indications,” news release, FDA; https://tinyurl.com/y8t4hh3a
