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Phase 3 EPCORE FL-1: epcoritamab plus R² in relapsed or refractory follicular lymphoma

In this global, open-label, randomised trial, epcoritamab plus R² was associated with higher response rates and longer progression-free survival than R² alone, with more frequent grade 3 or higher adverse events reported for the triplet.

  • Lorenzo Falchi, MD; Marcel Nijland, MD; Huiqiang Huang, MD; Kim M Linton, PhD; John F Seymour, PhD; Rong Tao, MD; et al.

  • December 7, 2025

  • The Lancet
  • The Lancet, Volume 407, Issue 10524, Pages 161–173
  • 10.1016/S0140-6736(25)02360-8

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Evidence before this study

We searched PubMed and major international congresses from July 1, 2015, to July 17, 2025, for randomised clinical trials published in all languages that evaluated relapsed or refractory follicular lymphoma treatments using the search terms “follicular lymphoma” AND (“relapsed” OR “refractory”) AND (“immunomodulatory” OR “lenalidomide”). From our searches, we found randomised phase 2 trials CALGB 50401 and HOVON110/Rebel and phase 3 trials AUGMENT, MAGNIFY, and inMIND. These studies supported the combination of lenalidomide and rituximab (R2) as an internationally accepted standard for individuals with relapsed or refractory follicular lymphoma. Although R2 offers a therapeutic option, only around half of treated patients have a complete response and most relapse, needing subsequent treatments. The additions of bendamustine in the HOVON110/Rebel trial and tafasitamab in the inMIND trial improved efficacy outcomes with no unexpected toxicities. Early-phase trials are evaluating novel agents in combination with R2 or immunomodulatory agent lenalidomide as chemotherapy-free options for follicular lymphoma after initial therapy. We hypothesised that the addition of epcoritamab with the R2 regimen would enhance efficacy and minimise overlapping toxicities. In preclinical studies, epcoritamab worked well in the presence of rituximab, and lenalidomide enhanced activation of immune cells. In the phase 1b/2 EPCORE NHL-2 trial (), fixed-duration epcoritamab plus R2 was evaluated in patients with relapsed or refractory follicular lymphoma, yielding deep and durable responses including an overall response rate of 96%, a complete response rate of 88%, and an estimated 24-month progression-free survival of 76%. On the basis of these results, the randomised, global, open-label, phase 3 EPCORE FL-1 trial () was initiated to evaluate the efficacy and safety of epcoritamab plus R2 versus R2 alone in individuals with relapsed or refractory follicular lymphoma.

Added value of this study

This EPCORE FL-1 trial is, to our knowledge, the first phase 3 study of a bispecific antibody combination therapy in individuals with follicular lymphoma to be reported, and showed that the combination of epcoritamab plus R2 significantly improved response rate and reduced the risk of disease progression or death compared with R2. Benefit was observed across all explored participant subgroups, underscoring the generalisability of these results in the broader relapsed or refractory follicular lymphoma population. Although adverse events of grade 3 or higher were more frequent with the triplet versus R2, these were manageable and consistent with the established safety profiles of the individual components of the triplet, with no new safety findings identified.

Implications of all the available evidence

In the landscape of studies in individuals with relapsed and refractory follicular lymphoma, epcoritamab and R2 stands as the first bispecific-based, off-the-shelf, outpatient, fixed-duration, efficacious second-line or later therapy to represent a new and improved chemotherapy-free standard of care in this population. Additionally, this regimen could be a more accessible and convenient treatment option associated with longer remission.

Source: The Lancet

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