Epcoritamab Triplet Improves Response and Survival in Relapsed or Refractory Follicular Lymphoma

Key Clinical Summary

• In the phase 3 EPCORE FL-1 trial (n = 488), epcoritamab plus lenalidomide and rituximab (R²) significantly improved outcomes vs R² alone in relapsed or refractory follicular lymphoma, including overall response rate (95% vs 79%) and complete response rate (83% vs 50%).
• The triplet demonstrated markedly prolonged progression-free survival (PFS) (HR 0.21), with median PFS not reached vs 11.7 months and superior durability of response.
• Grade ≥3 adverse events were higher (90% vs 68%), driven by neutropenia and infections; cytokine release syndrome (35%) was mostly low grade and manageable.

Epcoritamab plus R² significantly improves response rates and PFS over R² alone, positioning the triplet as a strong new chemotherapy-free option for relapsed or refractory follicular lymphoma, according to study results published in The Lancet.

Fixed-duration epcoritamab plus R² showed deep and durable reponses in the phase 1b/2 EPCORE NHL-2 trial.

“On the basis of these encouraging results, the randomised phase 3 EPCORE FL-1 trial (NCT05409066, EudraCT 2021-000169-34)—comparing the efficacy and safety of epcoritamab plus R2 vs R2 alone in participants with relapsed or refractory follicular lymphoma after at least one previous line of chemoimmunotherapy—was initiated,” explained the authors.

The EPCORE FL-1 study enrolled 488 patients at 189 centers in 30 countries. Participants were randomized to receive either epcoritamab plus R² (n = 243) or R² alone (n = 245). The study population included a clinically challenging mix of patients: 44% had a follicular lymphoma international prognostic index (FLIPI) score of 3 or higher, 22% had bulky disease, 37% were double refractory to prior anti-CD20 antibodies and alkylating agents, and 41% had progression within 24 months of first-line chemoimmunotherapy.

At a median follow-up of 14.8 months, the triplet met both primary endpoints. The overall response rate was 95% with epcoritamab plus R² compared with 79% for R² alone, while the complete response rate was 83% vs 50%. Responses also appeared more durable: the 12-month duration of response was 89.2% with the triplet vs 48.5% with R², and the 12-month duration of complete response was 91.2% vs 56.0%.

Median PFS was not reached in the epcoritamab arm, compared with 11.7 months for R² alone, translating to a 79% reduction in the risk of progression or death (HR 0.21, 95% CI 0.14-0.31; P < .0001). At 16 months, PFS was 85.5% with epcoritamab plus R² vs 40.2% with R2. Median time to next antilymphoma treatment was also not reached with the triplet, while the 16-month estimate was 92.8% vs 64.9% for R² alone. Overall survival data remain immature, but the 16-month overall survival rate was 95.8% with epcoritamab plus R² and 88.8% with R².

Toxicity was higher with the triplet but manageable. Grade ≥3 adverse events occurred in 90% with epcoritamab plus R2 vs 68% with R², mainly due to neutropenia (69% vs 42%) and infections (33% vs 16%). Cytokine release syndrome occurred in 35% but was low grade.

“In the new era of chemotherapy-free options providing longer remission and potential cure, epcoritamab plus R2 is positioned to replace R² as the new standard of care for second-line or subsequent treatment of follicular lymphoma,” concluded the study authors.

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