Epcoritamab Plus Rituximab/Lenalidomide, Epcoritamab Maintenance Both Deliver Durable Remissions in First-Line Follicular Lymphoma

Treatment with the combination of epcoritamab-bysp (Epkinly), rituximab (Rituxan), and lenalidomide (R²), as well as epcoritamab monotherapy following standard-of-care (SOC) induction therapy, yielded durable remissions in patients with first-line follicular lymphoma, according to 3-year data from arms 6 and 7 of the phase 1b/2 EPCORE NHL-2 trial (NCT04663347).¹

Findings presented at the 2025 ASH Annual Meeting and Exposition demonstrated that in arm 6, patients treated with epcoritamab plus R² (n = 41) achieved an overall response rate (ORR) of 95%, including a complete response (CR) rate of 88% and a partial response (PR) rate of 7%; all evaluable patients (n = 26) had minimal residual disease (MRD)–negative disease at a 10^-5 sensitivity. Five percent of patients were not evaluable for response. Among the 36 patients to reach CR, 10 discontinued treatment for reasons other than progressive disease or death; 9 of these 10 patients maintained CR. In the 21 patients who completed treatment while in CR, the response was maintained in 20 patients. The median duration of CR (DOCR) was not reached (NR). The median progression-free survival (PFS) and overall survival (OS) were both NR (95% CI, NR-NR). The median time to next treatment was also NR, with an estimated 97% of patients (95% CI, 83%-100%) free from new anti-lymphoma treatment.

Among patients in arm 7 treated with epcoritamab maintenance following SOC therapy (n = 19), 58% had a CR as best response to prior therapy, and 42% had a PR as best response. All patients in PR from their last line of therapy converted to CR after a median of 2.8 months (range, 2.5-5.7) of treatment with epcoritamab maintenance. The median DOR and DOCR were both NR in this cohort, with 84% of patients still in response and 84% of patients still alive at 33 months. For the 10 patients who completed study treatment, all had a CR at the end of treatment; these CRs were maintained at a median follow-up of 12.2 months. The median PFS and OS were both NR.

“These data support the continued development of epcoritamab for frontline follicular lymphoma, and [the combination] is being further investigated in the phase 3 EPCORE FL-2 trial [NCT06191744],” lead study author Lori A. Leslie, MD, said in a presentation of the data.

Leslie is an assistant professor at the Hackensack Meridian School of Medicine and director of the Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs at Hackensack Meridian Health in New Jersey.

What was the design of the EPCORE NHL-2 trial?

In November 2025, the FDA approved the combination of epcoritamab and R2 for the treatment of patients with relapsed or refractory follicular lymphoma, while simultaneously granting traditional approval to epcoritamab monotherapy for the treatment of patients with relapsed/refractory follicular lymphoma who have received at least 2 prior lines of therapy.²

After the phase 3 EPCORE FL-1 trial (NCT05409066) evaluated the combination and the phase 1/2 EPCORE NHL-1 trial (NCT03625037) examined epcoritamab monotherapy, supporting the respective approvals in the relapsed/refractory settings, arms 6 and 7 of EPCORE NHL-2 sought to evaluate the efficacy and safety of these regimens as part of earlier lines of therapy.^1-3

EPCORE NHL-2 enrolled patients with grade 1, 2, or 3A, CD20-positive follicular lymphoma who had an ECOG performance status of 0 to 2 and adequate organ function.¹ In arm 6, patients needed to have first-line follicular lymphoma with measurable disease per CT/MRI, and they needed to meet Groupe d'Etude des Lymphomes Folliculaires criteria. In arm 7, patients needed to be in CR or PR following 1 to 2 lines of SOC therapy.

Patients in arm 6 received epcoritamab at 48 mg once every 4 weeks in cycle 3 and beyond, following once-per-week step-up dosing in cycles 1 and 2. Treatment continued for up to 2 years. They were also administered lenalidomide at 20 mg once per day for 21 days in cycles 1 through 12 plus rituximab at 375 mg/m² once per week in cycle 1, then once every 4 weeks in cycles 2 to 6.

Those in arm 7 received epcoritamab at 48 mg once every 8 weeks in cycles 2 to 13 following once-per-week step-up dosing in cycle 1. Treatment continued for up to 2 years.

The primary end points for arm 6 and arm 7 were ORR and safety, respectively. Secondary end points in arm 6 included safety, DOR, DOCR, PFS, OS, and MRD-negativity rate. CR rate and DOCR were key secondary end points for arm 7.

At the April 9, 2025, data cutoff, the median follow-up was 36 months (range, 1-42) for arm 6 and 35 months (range, 6-39) for arm 7.

In arm 6, the median age was 57 years (range, 39-78), and 51% of patients were male. Most patients had an ECOG performance status of 0 (83%), had Ann Arbor stage IV disease (68%), did not have bulky disease of 7 cm or greater (68%), had normal lactate dehydrogenase levels (76%), and had normal beta-2 microglobulin levels (54%). Patients received a median of 24 cycles of epcoritamab (range, 1-27), 6 cycles of rituximab (range, 1-6), and 12 cycles of lenalidomide (range, 1-12). The maximum number of cycles of the respective agents were administered to 68%, 83%, and 63% of patients. Fifty-six percent of patients completed treatment per protocol, and reasons for discontinuation included adverse effects (AEs; 34%), patient withdrawal (5%), progressive disease (2%), and other (2%).

In arm 7, the median age was 56 years (range, 31-78), and 58% of patients were male. Eighty-four percent had an ECOG performance status of 0. Patients received the first dose of study treatment at a median of 2.8 months (range, 1.2-6.0) following the last dose of SOC induction therapy. Prior systemic therapies included anti-CD20 agents (100%) and a bendamustine-containing regimen (16%). Most patients (84%) received 1 prior line of therapy.

Patients in arm 7 received a median of 11 cycles of epcoritamab (range, 2-13), with a median treatment duration of 21 months (range, 1-24). Fifty-three percent of patients completed protocol treatment, and reasons for discontinuation comprised AEs (21%), patient withdrawal (16%), progressive disease (5%), and other (5%).

What safety data were reported from EPCORE NHL-2?

In arm 6, serious infections occurred in 32% of patients (n = 13), with 7 patients experiencing these infections in the first 24 weeks of treatment. Five grade 5 serious infections were reported. Neutropenia occurred at grades 1, 2, 3, and 4 at rates of 5%, 7%, 27%, and 22%, respectively. Leslie noted that neutropenia occurred at the highest rates during the first 24 weeks of treatment, and no instances of febrile neutropenia were reported. Cytokine release syndrome (CRS) occurred at grade 1 in 46% of patients and grade 2 in 15% of patients. No grade 3 or higher CRS was reported, and all instances were resolved with supportive care and no treatment discontinuations.

Long-term data showed the incidence of grade 3 or higher treatment-emergent AEs (TEAEs) declined over time. With 13 months of additional follow-up, 1 new instance of grade 3 COVID-19 was reported, and pneumonia led to treatment discontinuation in 2 patients. One death due to progressive multifocal leukoencephalopathy was reported.

For epcoritamab in arm 7, no grade 5 TEAEs occurred. Among the 8 serious infections reported, 6 were COVID-19. The respective rates of grades 1, 2, 3, and 4 neutropenia were 5%, 11%, 11%, and 11%, with no febrile neutropenia reported. CRS occurred at grade 1 in 37% of patients and grade 2 in 16% of patients. No grade 3 or higher CRS occurred, and all instances resolved without treatment discontinuations. With long-term follow-up, 1 additional instance of grade 3 COVID-19 was reported, and 1 patient died due to an unknown cause, although this was classified as a non-TEAE–related death.

References

1. Leslie L, Musuraca G, Abrisqueta P, et al. Epcoritamab with rituximab + lenalidomide (R2) and epcoritamab maintenance deliver deep and durable remissions in previously untreated (1L) follicular lymphoma (FL): 3-year outcomes from EPCORE NHL-2 arms 6 and 7. Blood. 2025;146(suppl 1):465. doi:10.1182/blood-2025-465
2. FDA approves epcoritamab-bysp for follicular lymphoma indications. FDA. November 18, 2025. Accessed December 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-epcoritamab-bysp-follicular-lymphoma-indications
3. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. FDA. June 26, 2024. Accessed December 16, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-epcoritamab-bysp-relapsed-or-refractory-follicular-lymphoma