Epcoritamab Combo Significantly Improves Efficacy in 2L R/R Follicular Lymphoma

The phase 3 EPCORE FL-1 trial showed that adding epcoritamab to R2 delivered superior PFS and response rates for patients with relapsed/refractory FL vs R2 alone.

Fixed-duration epcoritamab (Epkinly) plus rituximab (Rituxan) and lenalidomide (Revlimid; R2) demonstrated significant improvements in progression-free survival (PFS) and response rates compared with R2 alone in patients with relapsed/refractory follicular lymphoma, according to findings from the phase 3 EPCORE FL-1 trial (NCT05409066) presented in a press briefing during the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.1,2

At a median follow-up of 14.8 months, results showed that the median PFS per independent review committee (IRC) was not estimable with epcoritamab (95% CI, NE-NE) plus R2 compared with 11.7 months (95% CI, 11.1-15.1) with R2 alone, leading to a 79% reduction in the risk of disease progression or death (HR, 0.21; 95% CI, 0.14-0.31; P <.0001). The concordance rate was 94% for PFS between IRC and investigator assessment. The estimated 16-month PFS rates were 85.5% (95% CI, 79.7%-89.7%) and 40.2% (95% CI, 31.8%-48.4%), respectively.

The epcoritamab regimen elicited a 95% objective response rate (ORR) compared with 79% with R2 alone (P <.0001). In the epcoritamab arm, the complete response (CR) rate was 83% and the partial response (PR) rate was 12%; 1 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.

“Epcoritamab 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 Lorenzo Falchi, MD, of the Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York, NY, said in the oral presentation. “We’re happy to see that the FDA granted full approval to epcoritamab and R2 on November 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 epcoritamab, a CD3xCD20 bispecific antibody, as a single agent for the treatment of patients with relapsed/refractory follicular lymphoma following at least 2 lines of systemic therapy.3

Early data from the phase 1b/2 EPCORE NHL-2 trial (NCT04663347), which evaluated fixed-duration epcoritamab plus R2 for relapsed/refractory follicular lymphoma, demonstrated deep and durable responses and a manageable safety profile.4

In November 2025, the FDA also approved epcoritamab 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.5 In the international, open-label, EPCORE FL-1 trial, patients underwent a 1:1 randomization to receive fixed-duration epcoritamab at 48 mg plus R2 (n = 243) or R2 alone (n = 245).

Epcoritamab was administered in a 3-step-up, 2-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 4 weeks. Rituximab was given at 375 mg/m2 for 5 cycles; the agent was given weekly in cycle 1 and every 4 weeks in cycles 2 through 5. Lastly, lenalidomide was given at 20 mg for 12 cycles; treatment was given daily in cycles 1 through 12 on days 1 through 21.

The dual primary end points were ORR and PFS, both per IRC; key secondary end points were CR rate per IRC, overall survival (OS), and minimal residual disease. Additional secondary end points were duration of response (DOR), duration of complete response, time to next lymphoma treatment (TTNLT), safety, and patient-reported outcome assessments.

The data cutoff date was May 24, 2025, and patients were enrolled between October 2022 and January 2025.

To be eligible for enrollment, patients had to have histologically confirmed CD20-positive follicular lymphoma that was grade 1 to 3a and stage II to IV. At least 1 prior treatment was required, including an anti-CD20 monoclonal antibody plus an alkylating agent, and at least 1 Groupe d'Etude des Lymphomes Folliculaires criterion needed to be met.

Patients were stratified by disease status in second line (> or ≤ 2 years since last therapy), third line (> or <6 months since last therapy), and region (US/EU vs rest of world).

Baseline characteristics showed that the median age was 61 years (range, 24-89), 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 III to IV 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 5 years (range, 0.1-43.0), and the median number of prior lines of therapy was 1 (range, 1-7), with most patients receiving 1 (59%), 2 (24%), or at least 3 (17%). All patients received a prior anti-CD20 antibody, and 3% had received prior R2. Forty-one percent of patients experienced disease progression within 2 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 epcoritamab plus R2 was NE (95% CI, NE-NE) compared with 11.5 months (95% CI, 8.5-18.6) with R2 alone (HR, 0.19; 95% CI, 0.12-0.30; P <.0001).

The epcoritamab regimen also extended TTNLT; the median was NE (NE-NE) compared with 24.3 months (95% CI, 18.2-NE) with R2 alone (HR, 0.15; 95% CI, 0.09-0.27; P <.0001). At 16 months, 92.8% of patients on epcoritamab plus R2 remained free from new anti-lymphoma therapy vs 64.9% of those on R2 alone.

Falchi noted there is a positive trend for OS with the epcoritamab arm, which is NE (95% CI, NE-NE) in both arms (HR, 0.38; 95% CI, 0.18-0.80; P = .0039), adding that there are 10 and 25 events in the epcoritamab and R2-alone arms, respectively. Sixteen-month estimates for OS were 95.8% for epcoritamab plus R2 vs 88.8% with R2 alone.

Regarding safety, any-grade adverse events occurred in 100% and 99% of patients on epcoritamab plus R2 and R2 alone, with grade 3 or higher AEs at 90% and 68%, respectively. Serious AEs occurred in 56% and 29%, respectively, and AEs that led to treatment discontinuation occurred in 19% and 12% of patients.

Any-grade and grade 3 or higher AEs of clinical interest occurring in at least 20% of patients on epcoritamab/R2 and R2 alone included infections (77% and 33% vs 53% and 16%), neutropenia (74% and 69% vs 52% and 42%), cytokine release syndrome (any-grade, 35% vs <1%) thrombocytopenia (28% and 9% vs 18% and 6%), pyrexia (24% and <1%; 14% and 1%), rash (24% and 8% vs 22% and 4%), and COVID-19 (22% and 3% vs 13% and 2%).

On the epcoritamab arm, 3% of patients discontinued due to neutropenia vs 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 epcoritamab and R2 and R2 alone experienced fatal AEs.

“Despite these higher rates of AEs in the epcoritamab and R2 arm, the median relative dose intensity was greater than 90%,” Falchi added.

Disclosures: Falchi cited consultancy, including expert testimony, with Johnson & Johnson, Roche, ADC Therapeutics, Evommune, F. Hoffman-La Roche Ltd., AbbVie, Sanofi, Genentech, AstraZeneca, Seagen, Merck, and Genmab; honoraria from Roche, Kite Pharma, F. Hoffman-La Roche Ltd., AbbVie, and Genmab; and research funding from Roche, F. Hoffman-La Roche Ltd., AbbVie, Innate Pharma, Genentech, BeiGene, AstraZeneca, and Genmab.

References

1. Falchi L, Nijland M, Huang H, et al. 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. Blood. 2025;146(supplement 1):466. doi:10.1182/blood-2025-466
2. Falchi L, Nijiland M, Huang H, et al. Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed/refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial. Lancet. Published online December 7, 2025. doi:10.1016/50140-6736(25)02360-8
3. EPKINLY™ (epcoritamab-bysp) injection prescribing information. FDA. Updated May 2023. Accessed December 7, 2025. https://tinyurl.com/mrvfmaur
4. Falchi L, Sureda A, Leppä S, et al. Fixed-duration epcoritamab plus R2 drives favorable outcomes in relapsed or refractory follicular lymphoma. Blood. 2025;146(22):2629-2640. doi:10.1182/blood.2025029909
5. FDA approves epcoritamab-bysp for follicular lymphoma indications. News release. FDA. November 18, 2025. Accessed December 7, 2025. https://tinyurl.com/y8t4hh3a