FDA Approval of Epcoritamab-Based Triplet Challenges Prior Standards for R/R Follicular Lymphoma

The addition of epcoritamab-bysp (Epkinly) to lenalidomide (Revlimid) plus rituximab (Rituxan) represents a new standard of care for patients with double-refractory follicular lymphoma and opens the door for broader clinical utility of bispecific antibodies in community oncology settings, according to Lorenzo Falchi, MD. 

On November 18, 2025, the FDA approved epcoritamab for use in combination with rituximab and lenalidomide for the treatment of patients with relapsed/refractory follicular lymphoma who have received 2 or more prior lines of therapy.¹ This regulatory decision was backed by data from the phase 3 EPCORE FL-1 trial (NCT05409066). Data that supported the approval showed that the triplet regimen generated a median progression-free survival (PFS) that was not reached (NR; 95% CI, 21.9 months-NR) compared with 11.2 months (95% CI, 10.5-NR) among patients who received rituximab plus lenalidomide alone (HR, 0.21; 95% CI, 0.13-0.33; P < .0001). Additionally, the overall response rate (ORR) was 89% (95% CI, 84%-93%) in the epcoritamab cohort vs 74% (95% CI, 68%-79%) in the control cohort (P < .0001).

“As is happening in other settings, bispecific antibodies, [epcoritamab] in this case, become the core therapy,” Falchi said in an interview with OncLive®.

In the interview, Falchi discussed the significance of this approval, expanded on efficacy findings from the primary analysis of EPCORE FL-1 that were presented at the 2025 ASH Annual Meeting, and noted how the safety profile of this regimen supports its future outpatient administration.

Falchi is an assistant attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What is the significance of the FDA approval of epcoritamab plus lenalidomide and rituximab for relapsed/refractory follicular lymphoma?

Falchi: The FDA approval of the combination of epcoritamab/lenalidomide/rituximab has a large resonance in many ways. Epcoritamab monotherapy also secured traditional approval for third- and later-line follicular lymphoma; this was a provisional approval before. Additionally, epcoritamab monotherapy is approved for DLBCL. More broadly, [we now have] a triplet combination that's entirely chemotherapy free in the second-line setting in follicular lymphoma that is substantially superior to rituximab plus lenalidomide in the contemporary era.

Patients with relapsed or refractory follicular lymphoma [now] are a bit different than [those with the disease] when the phase 3 AUGMENT study [(NCT01938001) of lenalidomide plus rituximab] was conducted. [The EPCORE FL-1] population included patients who were primary refractory or double refractory and had high-risk features. [This regimen] provides a solid new benchmark. This is the new benchmark for second-line and later follicular lymphoma management, against which probably any new therapies should be compared.

There's a similar study, the phase 3 inMIND study [NCT04680052], findings from which were presented [in 2024], comparing rituximab/lenalidomide with or without tafasitamab [in patients with relapsed/refractory follicular lymphoma]. In that study, which was also positive, the addition of tafasitamab prolonged PFS and mean response rate [vs placebo plus lenalidomide and rituximab]. Intertrial comparisons are always discouraged. We had differences between the baseline characteristics of our patient populations. But one cannot help but look at the effect size of the addition of epcoritamab vs the addition of other drugs like tafasitamab [to lenalidomide plus rituximab].

Epcoritamab here is the core therapy, not lenalidomide plus rituximab. Most of the benefit for these patients is derived from the bispecific antibody. These drugs are transformative in the setting of B-cell non-Hodgkin lymphoma.

What efficacy findings from EPCORE FL-1 were presented at ASH 2025?

The study met both its primary end points. The addition of epcoritamab to lenalidomide plus rituximab led to a 79% reduction in the risk of progression or death compared with lenalidomide plus rituximab alone. The HR for that comparison was [0.21], with a higher statistical significance at 16 months, which is the point we chose for our estimates. The [16-month] PFS rate was 85.5% [95% CI, 79.7%-89.7%] in the epcoritamab/lenalidomide/rituximab arm and 40.2% [95% CI, 31.8%-48.4%] for lenalidomide/rituximab alone.

The other primary end point, ORR, was also met, at 95% vs 79% for epcoritamab/lenalidomide/rituximab vs lenalidomide/rituximab alone. That carried along with it an advantage in complete response rate, at 83% vs 50%, respectively. The durations of both objective and complete responses were also significantly longer in the epcoritamab/lenalidomide/rituximab arm compared with the lenalidomide/rituximab alone. Another key secondary end point we evaluated that was encouraging to see was that the time to next line of treatment was much prolonged with epcoritamab/lenalidomide/rituximab, where [92.8]% of patients were free from receiving a subsequent line of therapy at 16 months. We also saw a positive trend for overall survival for epcoritamab/lenalidomide/rituximab, where [95.8]% of patients were alive at the 16-month mark.

What is the safety profile of epcoritamab plus lenalidomide and rituximab in relapsed/refractory follicular lymphoma?

Adding epcoritamab, not unexpectedly, resulted in additional adverse effects [AEs]. Chiefly, [we saw] cytokine release syndrome [CRS], which is a bispecific antibody–associated AE. Neutropenia and infections were also a bit more frequent with the addition of epcoritamab. However, these were all manageable. Uncommonly did they lead to hospitalization. Even less commonly did they result in treatment discontinuation or an impairment to the treatment deliverability.

The median relative dose intensity of epcoritamab/lenalidomide/rituximab was [at least] 90%, suggesting that although there are AEs, in the hands of hematologists who are well versed in managing cytopenias and infectious complications, this treatment can be delivered almost to its fullest. Importantly, this regimen was delivered on an outpatient basis. The rate of CRS was 45% in patients treated with epcoritamab administered with 2 step-up doses.³

Midway through the study, we implemented 3 step-up doses, adding an extra intermediate dose of 3 mg on cycle 1 day 15. That resulted in an even lower incidence of CRS, at 26%, including a decrease in both grade 1 and grade 2 CRS; [the rate of grade 2 CRS] in the 3 step-up doses cohort was 5%, and there were no grade 3/4 [CRS] events. These data support the fully outpatient administration of epcoritamab/lenalidomide/rituximab. This is important, particularly for our colleagues in the community who may not have immediate access to large referral centers or even hospitals where patients can be admitted.

References

1. FDA approves epcoritamab-bysp for follicular lymphoma indications. FDA. November 18, 2025. Accessed January 14, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-epcoritamab-bysp-follicular-lymphoma-indications
2. Falchi L, Nijland M, Huang H, et al. Primary phase 3 results from the epcore FL-1 trial of epcoritamab with rituximab and lenalidomide (R2) versus R2 for relapsed or refractory follicular lymphoma. Blood. 2025;146(suppl 1):466. doi:10.1182/blood-2025-466
3. 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