Dr Falchi on the Significance of the FDA Approval of Epcoritamab Plus Rituximab/Lenalidomide for R/R Follicular Lymphoma

“I think having a triplet combination that's entirely chemotherapy free in the second line, you know, spacing follicular lymphoma that is very substantially superior to rituximab and lenalidomide.”

Lorenzo Falchi, MD, a medical oncologist /hematologist and assistant attending physician in the Lymphoma Service at Memorial Sloan Kettering Cancer Center, discussed the clinical and regulatory significance of the FDA approval of epcoritamab-bysp (Epkinly) plus rituximab (Rituxan) and lenalidomide (Revlimid; R²) for the treatment of patients with relapsed or refractory follicular lymphoma, highlighting how this decision reshapes the second-line treatment landscape.

On November 18, 2025, the approved the combination for the treatment of patients with relapsed or refractory follicular lymphoma; of note, traditional approval was also granted to epcoritamab monotherapy for the treatment of patients with relapsed/refractory follicular lymphoma who received at least 2 prior lines of therapy.

The approval of epcoritamab plus R² was supported by results from the randomized phase 3 EPCORE FL-1 trial (NCT05409066), which met both its overall response rate (ORR) and progression-free survival (PFS) end points. In a prespecified interim analysis, the epcoritamab-based triplet demonstrated a 79% reduction in the risk of disease progression or death compared with rituximab plus lenalidomide alone (HR, 0.21; 95% CI, 0.13-0.33; P < .0001). The median PFS was not reached (NR) in the epcoritamab arm (95% CI, 21.9-NR) vs 11.2 months (95% CI, 10.5-NR) in the control arm. The combination also produced an ORR of 89% (95% CI, 84%-93%) compared with 74% (95% CI, 68%-79%) for rituximab and lenalidomide alone; this improvement was statistically significant (P < .0001).

Falchi emphasized that beyond the numerical improvements in efficacy, this regimen has broader implications for the management of follicular lymphoma. Most notably, the FDA approval brings a highly effective, entirely chemotherapy-free triplet regimen into the second-line setting. In the current treatment era, patients with relapsed or refractory follicular lymphoma often present with more aggressive disease characteristics than those enrolled in earlier studies, such as the phase 3 AUGMENT trial (NCT01938001), including primary refractory disease, double refractoriness, and other high-risk features. Against this backdrop, the magnitude of benefit observed with epcoritamab plus R² represents a meaningful advance, Falchi emphasized.

He also noted that the accompanying full approval for epcoritamab monotherapy reinforces its role in later-line follicular lymphoma and diffuse large B-cell lymphoma. From a clinical perspective, the availability of a bispecific antibody–based regimen in combination with established immunomodulatory and anti-CD20 therapy offers a new standard against which future second-line strategies are likely to be compared.

Falchi concluded that the results from EPCORE FL-1 set a new benchmark for efficacy in relapsed or refractory follicular lymphoma. In his view, the combination of epcoritamab and R² is poised to become a reference regimen in the second-line and beyond, providing a strong foundation for both clinical practice and ongoing therapeutic development in this disease space.