Epcoritamab Plus Lenalidomide and Rituximab Improves PFS in Relapsed Follicular Lymphoma

Key Clinical Summary

• Phase 3 EPCORE FL-1 trial met dual primary endpoints, demonstrating superior overall response rate (95% vs 79%) and progression-free survival (PFS) with epcoritamab plus lenalidomide and rituximab (R2) vs R2 alone.
• Estimated 16-month PFS was 85.5% with the triplet vs 40.2% with R2 (HR 0.21; P <.0001).
• Grade ≥3 adverse events were more frequent with the triplet (90% vs 68%), but cytokine release syndrome was low grade and manageable.

Relapsed or refractory follicular lymphoma remains an area of unmet need, particularly for durable, chemotherapy-free regimens. In the global phase 3 EPCORE FL-1 trial (NCT05409066), fixed-duration epcoritamab plus R2 demonstrated superior efficacy compared with R2 alone in patients previously treated with at least 1 line of chemoimmunotherapy.

Study Findings

EPCORE FL-1 is a multicountry, open-label, randomized phase 3 study conducted across 189 academic and non-academic centers in 30 countries. A total of 488 patients with relapsed or refractory follicular lymphoma were randomly assigned 1:1 to receive epcoritamab plus R2 (n = 243) or R2 alone (n = 245) for up to 12 cycles.

The trial met its dual primary endpoints of overall response rate (ORR) and PFS, assessed by independent review committee per 2014 Lugano criteria. At a median follow-up of 14.8 months (IQR 11.4-19.0), ORR was significantly higher in the epcoritamab plus R2 arm at 95% (95% CI, 92-97) compared with 79% (74-84) in the R2 arm (P < .0001).

PFS was markedly prolonged with the triplet regimen. The HR for disease progression or death was 0.21 (95% CI, 0.14-0.31; P < .0001), corresponding to a 79% reduction in risk. Estimated 16-month PFS was 85.5% in the epcoritamab group vs 40.2% with R2 alone.

The complete response rate reached 83% with epcoritamab plus R2, described as deep and durable. Benefit was observed across all prespecified subgroups. Time to next antilymphoma treatment was also longer in the triplet arm. Although overall survival follow-up remains short, deaths due to disease were lower with epcoritamab plus R2.

Grade 3 or higher adverse events occurred in 90% of patients receiving the triplet compared with 68% in the R2 arm. Cytokine release syndrome was reported as low grade (grade 1 in 21% and grade 2 in 5%) and was manageable, with all events resolved. No new safety signals were identified.

Clinical Implications

For payers and managed care stakeholders, the findings position epcoritamab plus R2 as a potential new standard of care for second-line or later follicular lymphoma. The substantial reduction in progression risk and high complete response rates may translate into prolonged remission and delayed need for subsequent therapies.

The regimen is chemotherapy-free and administered in the outpatient setting, aligning with broader oncology trends favoring targeted and immunotherapy-based combinations. Although higher rates of grade ≥3 adverse events were observed, the safety profile was consistent with known effects of the individual agents and manageable in clinical practice.

From a health system perspective, longer progression-free intervals and extended time to next treatment could affect cost offsets, treatment sequencing, and resource utilization. Ongoing follow-up will be important to clarify durability, minimal residual disease outcomes, patient-reported outcomes, and long-term survival impact.

Investigators described EPCORE FL-1 as the first reported phase 3 study of a bispecific antibody combination therapy in relapsed or refractory FL. The combination “resulted in a deep and durable complete response rate of 83% and reduced the risk of disease progression or death by 79% compared with R2,” with adverse events “manageable and consistent with the established safety profiles of the individual components.”

Conclusion

In relapsed or refractory follicular lymphoma, epcoritamab plus R2 significantly improved response rates and PFS vs R2 alone. With durable remissions and a manageable safety profile, the triplet regimen is positioned to redefine second-line and later treatment standards in this population.

Reference

Falchi L, Nijland M, Huang H, et al. Epcoritamab, lenalidomide, and rituximab versus lenalidomide and rituximab for relapsed or refractory follicular lymphoma (EPCORE FL-1): a global, open-label, randomised, phase 3 trial. Lancet. 2026;407(10524):161-173. doi: 10.1016/S0140-6736(25)02360-8