Taking a Look at the Toxicity Trade-Offs of EPCORE FL-1

Among the headliners at the December 2025 meeting of the American Society of Hematology was the phase 3 EPCORE FL-1 trial (NCT05409066), which presenter Lorenzo Falchi, MD, of Memorial Sloan Kettering Cancer Center, heralded as a “new benchmark” in treating follicular lymphoma (FL).^1,2

The trial added the bispecific antibody epcoritamab (Epkinly; AbbVie/Genmab) to the combination of rituximab (Rituxan) and lenalidomide (Revlimid), known as R², to treat patients with FL as early as the first relapse. Results showed a huge leap in efficacy that study authors said should allow the combination to make it into community practice. Falchi’s presentation came less than a month after the FDA had approved the combination for patients who had received at least 1 systemic therapy.³

Now, an article in Frontiers in Oncology offers a critical appraisal of the EPCORE FL-1 trial.⁴ While authors Qinghua Ke and Shiqiong Zhou, both of the Department of Chemoradiotherapy, The First People’s Hospital of Jingzhou, in Hubei, China, acknowledge the trial as a landmark achievement, they make the case that the efficacy results must be weighed against a substantially more toxic safety profile.

What Was the Reduction in Disease Progression?

The EPCORE FL-1 trial hit many milestones, starting with the fact that it offered the first findings for a bispecific antibody in this setting. It delivered results that are “remarkable by any measure,” the authors wrote; the combination with the standard R² regimen produced a 79% reduction in the risk of disease progression or death (HR, 0.21).^1,4

Adding epcoritamab more than doubled 16-month progression-free survival estimates to 85.5%, vs 40.2% for R² alone.¹ The complete response rate nearly doubled, rising from 50% to 83%, and these gains were consistent even in high-risk subgroups such as patients whose disease progressed within 24 months, or those with double-refractory disease.^1,4

How is this possible? The authors attribute the biological plausibility of this triplet to epcoritamab's ability to bind a distinct CD20 epitope from rituximab, enabling simultaneous T-cell engagement without competitive interference. Preclinical data also demonstrated enhanced natural killer cell activation, supporting the synergy observed clinically.⁴

But Then, There Is the Toxicity Problem

Alongside these impressive outcomes, the authors write, there is the reality of what they call “the toxicity ceiling.” They explain that adverse events (AEs) of grade 3 or higher occurred in 90% of patients receiving the triplet versus 68% in the control arm. Most concerning were infectious complications, with grade 3 or higher infections seen in 33% of epcoritamab-R² recipients compared with just 15% in the R²-alone group, and opportunistic infections—particularly cytomegalovirus and herpes virus—seen in 18% vs 4%. The authors note that 19% of patients on the experimental arm discontinued treatment due to AEs, primarily infections.

Despite claims that this regimen is well-suited to a community practice setting, these results raise questions about whether patients less carefully selected than trial participants can realistically complete the intended 12-cycle course. Practices engaged in value-based risk arrangements with payers will have to weigh whether they have adequate patient monitoring systems to prevent AEs alongside watching for cytokine release syndrome (CRS) and other issues.

The authors are candid about whether these toxicities will prove manageable in real-world populations. The trial enrolled patients with a median age of 60 to 63 years and good performance status, excluding those with significant comorbidities, they noted. Community oncology practices treating older adults with cardiovascular disease, renal impairment, or baseline cytopenias are likely to encounter higher rates of treatment discontinuation or infectious mortality.⁴

“Subcutaneous administration facilitates outpatient delivery, but requirements for CRS monitoring, infection prophylaxis, and management of prolonged cytopenias demand health care infrastructure not universally available,” the authors write. “In low resource settings where R² alone may already be inaccessible, adding a costly bispecific antibody risks widening disparities. Cost-effectiveness analyses will be essential to guide reimbursement decisions and prioritization within national formularies.”⁴

What Are the Open Questions?

The open-label trial design, while practical, requires patients when waiting for AE data to accumulate. In particular, the overall survival (OS) data remain immature, with only 24% of required events observed. The authors caution that the current OS HR of 0.38, though favoring epcoritamab-R², reflects early separation driven largely by fewer progression-related deaths, and it remains unclear "whether this translates into durable survival advantage or merely delays progression without altering ultimate outcomes."

The authors also highlight that the control arm's PFS of 11.7 months is much shorter than the 39.4 months seen in the AUGMENT trial, the original study comparing the R² combination against lenalidomide alone in R/R indolent lymphoma.⁵ Indeed, they clarify this is not a flaw but a reflection of the considerably higher-risk population enrolled in EPCORE FL-1, and they caution against using this difference to undervalue R² in lower-risk relapsed settings.

Comparing epcoritamab-R² with other emerging options, the authors assert that it offers deeper responses than tafasitamab-R² but carries higher toxicity. Relative to chimeric antigen receptor (CAR) T-cell therapy, it provides an immediately available, fixed-duration alternative without the logistical complexity, though questions remain about whether prior bispecific antibody treatment affects subsequent CAR-T efficacy.

What is needed, the authors say, are the following⁴:

• longer follow-up to confirm durable remissions,
• biomarker studies to predict infection risk or treatment benefit, and
• dedicated studies in bendamustine-exposed and elderly populations.

The authors also call for adoption of guidelines—citing those issued by the British Society for Hematology—to help clinicians manage infectious complications and incorporate immunoglobulin replacement, which was not required in EPCORE FL-1.

What comes next, the authors say, is translating the trial results into learning which patients are the best candidates for the combination relative to the toxicity burden. They suggest the ideal candidate is likely a younger, fitter patient, especially who has progressed in less than 24 months, who can tolerate the infectious burden in exchange for a high complete response rate.

“The challenge for clinicians will be translating this benefit to real-world patients while mitigating the accompanying toxicity burden—a balance that will define whether this regimen becomes universally adopted or reserved for carefully selected candidates,” they write.⁴

References

1. 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) 407:161–73. doi: 10.1016/S0140-6736(25)02360-8
2. Caffrey M. EPCORE FL-1: Adding epcoritamab to R2 delivers “new benchmark” in second-line follicular lymphoma. Am J Manag Care. 2026;32(Spec 1):SP 30.
3. Caffrey M. Epcoritamab with rituximab plus lenalidomide approved for R/R follicular lymphoma in second line. AJMC. November 18, 2025. Accessed May 8, 2026. https://www.ajmc.com/view/epcoritamab-with-rituximab-plus-lenalidomide-approved-for-r-r-follicular-lymphoma-in-second-line
4. Ke Q, Zhou S. Epcoritamab plus R² in follicular lymphoma: practice-changing efficacy meets unresolved toxicity trade-offs. Front. Oncol. 2026;16:1811781. Published March 24, 2026. doi: 10.3389/fonc.2026.1811781
5. Leonard JP, Trneny M, Izutsu K et al; AUGMENT investigators. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188-1199. doi:10.1200/JCO.19.00010