How Will EPCORE FL-1 Subgroup Data Impact R/R Follicular Lymphoma Care?

The phase 3 EPCORE FL-1 trial (NCT05409066) established epcoritamab-bysp (Epkinly) plus lenalidomide (Revlimid) and rituximab (Rituxan)—known as the R² regimen—as a fixed-duration treatment with superior efficacy over R² alone in patients with relapsed/refractory follicular lymphoma, based on the dual primary end points of objective response rate (ORR) and progression-free survival (PFS) per independent review committee assessment.¹ At a median follow-up of 14.8 months, the combination reduced the risk of disease progression or death by 79% compared with R² alone (HR, 0.21; 95% CI, 0.14-0.31; P <.0001), with a complete response (CR) rate of 83% vs 50%.

CancerNetwork® spoke with Benoit Tessoulin, MD, PhD, hematologist at Centre Hospitalier Universitaire de Nantes, Nantes, France, and presenting author of the EPCORE FL-1 subgroup analysis at the European Hematology Association (EHA) 2026 Congress, about what the clinically relevant subgroup data reveal regarding the breadth of benefit with this combination.²

Tessoulin began by describing the rationale and scope of the subgroup analysis presented at EHA 2026, then reviewed key efficacy findings across patient- and disease-level subgroups. He then addressed the safety profile of the triplet across age and comorbidity strata before discussing the implications of these data for high-risk and early-relapse populations and the role of fixed-duration vs continuous maintenance strategies. He concluded by sharing his view on whether epcoritamab plus R² represented the preferred second-line standard of care for patients with relapsed/refractory follicular lymphoma.

CancerNetwork: Can you provide some background on the subgroup analysis from the EPCORE FL-1 trial that you presented at EHA 2026?

Tessoulin: The main background was that the EPCORE FL-1 trial demonstrated improved disease control in terms of PFS and [ORR] with the new combination of epcoritamab plus R² compared with R² alone in patients with relapsed or refractory follicular lymphoma, with a magnitude of 0.21 in terms of hazard ratio. The whole point of this subgroup analysis was to ask whether that benefit holds true across different kinds of patients, both in terms of patient-level risk factors and disease characteristics.

What were some of the key efficacy findings from the subgroup analysis?

The question we asked was whether the subgroup analyses held true across all kinds of patients in terms of disease risk and patient risk. When you look at the patient side—including age, comorbidity burden—and from the disease point of view—the number of prior lines of therapy, tumor size, POD24 [progression of disease within 2 years of initiating frontline therapy] status, and other factors—the hazard ratios across all of these subgroups sit between 0.2 and 0.3, perfectly aligned with the overall population result. In summary, all subgroups derived a benefit from epcoritamab plus R² compared with R² alone.

Were there any unique or unexpected toxicities that emerged with the epcoritamab-based regimen across your subgroup analyses?

The known safety profile from the main publication showed a slight increase in toxicities in the epcoritamab plus R² arm overall, but these were all [quite] manageable. In the subgroup analysis, when we looked specifically at patient profiles in terms of age and comorbidity burden, there were no meaningful differences among patients in terms of tolerance. This is a combination that could be a good fit for a broad range of patients.

Given how challenging high-risk and early-relapse subgroups have historically been to treat, how do you see this fixed-duration triplet reshaping frontline relapse management for these patients?

Within the trial population, we do not have a head-to-head comparison of PFS between low- and high-risk patients—we only have the comparison with the standard R² arm. It is somewhat difficult to ascertain the magnitude of relative benefit. But when you look at the subgroup analyses, you see that patients [who are deemed high risk]—those with POD24, for instance—derive a meaningful benefit compared with R² alone. This fixed-duration approach is a good option for [patients] at first relapse or even further, even if they are very high risk.

Do you believe a fixed-duration approach is sufficient to achieve long-term treatment-free remissions across all patients, or are there specific subgroups that might still benefit from a continuous maintenance strategy?

The data we currently have do not allow us to answer that question definitively. But patients are genuinely looking for fixed-duration treatment, and in that respect, the 12-cycle fixed-duration regimen is a good [option] for them. Even if patients eventually relapse, there will be additional lines of therapy available, and continuous maintenance is not necessarily the direction I see this field heading for these patients.

For a patient experiencing a relapse after first-line chemoimmunotherapy, would you consider epcoritamab plus R² to be the preferred second-line standard of care?

Compiling all the data in the field now, this combination has demonstrated the best outcomes in terms of long-term disease control. The follow-up, however, was relatively short at 14.8 months, so we need to wait for more mature data. For now, it is a good option, and the main analysis even showed a slight benefit in terms of overall survival, which is quite unique in the follicular lymphoma world. We will be watching for the updated data to emerge.

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(10524):161-173. doi:10.1016/S0140-6736(25)02360-8
2. Nijland M, Falchi L, Linton K, et al. Clinically relevant subgroup analysis from the randomized phase 3 EPCORE FL-1 trial: treatment effect of epcoritamab with lenalidomide and rituximab in R/R follicular lymphoma. Presented at: European Hematology Association Annual Meeting; June 11–14, 2026; Stockholm, Sweden. Abstract S229.