Moving Bispecific Antibodies Earlier in Follicular Lymphoma
- The EPCORE-FL1 study shows that adding the bispecific antibody epcoritamab to R² produces exceptionally high and durable responses in relapsed/refractory follicular lymphoma within a chemo-free, fixed-duration regimen. The combination drove a striking improvement in progression-free survival versus R² alone, improving PFS from 57% to 91%.
- Epcoritamab + R² produced exceptional activity, with ORR ~95-96% and CR rates ~83-88% in relapsed/refractory FL, including patients with high-risk features such as primary refractory disease and POD24.
- The combination significantly improved progression-free survival versus R² alone, reducing the risk of progression or death by ~79%, with many patients remaining treatment-free at follow-up.
- Toxicities were consistent with known effects; CRS was mostly low-grade and resolved, while higher-grade events (e.g., neutropenia, infections) were more frequent but generally manageable.
Although many patients achieve durable remissions with frontline therapy for follicular lymphoma (FL), relapse is expected for the majority, necessitating repeated lines of treatment over a prolonged disease course. In the second-line setting, rituximab plus lenalidomide (R²) has been widely adopted as a chemotherapy-free standard. Although R² is an established option, many patients do not achieve deep or durable remissions, highlighting the need for more effective therapies earlier in the disease course.
“Follicular lymphoma is the most common indolent, or ‘lazy,’ lymphoma, and while some patients can be monitored expectantly, many eventually need therapy based on disease burden, symptoms, or transformation risk,” Dr. Catherine Diefenbach, Director of the Clinical Lymphoma Program at NYU Langone’s Perlmutter Cancer Center, tells SurvivorNet Connect.
Epcoritumab is a subcutaneously administered CD20×CD3 bispecific T-cell engager. When combined with rituximab and lenalidomide, the regimen integrates direct T-cell cytotoxicity with antibody-mediated and immunomodulatory mechanisms, offering a fixed-duration, chemotherapy-free strategy for patients with relapsed or refractory FL after at least one prior systemic therapy.
New research shows the combination drove a striking improvement in progression-free survival versus R² alone.
Pivotal Phase 3 Evidence: EPCORE FL-1
The phase 3 EPCORE FL-1 trial (NCT05409066) was a randomized, open-label study comparing epcoritamab plus R² with R² alone in 488 patients with relapsed or refractory FL. Patients had received a median of one prior line of therapy, with approximately 24% having received two or more prior lines.
Epcoritumab plus R² demonstrated marked improvements across all major efficacy endpoints.
- Progression-free survival (PFS) was significantly prolonged, with a hazard ratio for disease progression or death of 0.21 (95% CI ~0.13–0.33; p<0.0001), corresponding to an approximately 79% reduction in risk compared with R² alone.
- Median PFS was not reached in the epcoritamab arm versus approximately 11.2-11.7 months with R², and estimated 16-month PFS rates were 85% and 40%, respectively.
In the full cohort analysis of EPCORE FL‑1, epcoritamab plus R² demonstrated superior efficacy compared with R² alone. At a median follow‑up of approximately 14.8 months, the overall response rate (ORR) was 95% with the triplet versus 79% with R² alone (p < 0.0001), and the complete response (CR) rate was 83% versus 50%, respectively.
PFS was significantly longer with epcoritamab plus R², with an estimated 16‑month PFS rate of 85.5% compared with 40.2% for R² and a hazard ratio of 0.21 for disease progression or death (p < 0.0001). These results reflect both high response rates and deep remissions with the addition of epcoritamab to the R² backbone.
Safety & Tolerability
The safety profile of epcoritamab plus R² was consistent with the expected immunologic effects of combining a bispecific antibody with immunomodulatory therapy. Cytokine release syndrome (CRS) occurred in approximately 24% of patients and was predominantly low grade, with most events reported as grade 1 and occurring early during step-up dosing; grade ≥3 CRS was infrequent. Immune effector cell-associated neurotoxicity syndrome (ICANS) was uncommon, occurring in approximately 0.8% of patients, with high-grade events rare.
Serious adverse reactions were reported in approximately 51% of patients, including serious infections in about 28%, reflecting cumulative immune suppression. Additional adverse events of interest included cytopenias, most commonly neutropenia, which were generally manageable with supportive care. Safety findings were consistent with prior experience using bispecific antibodies, and step-up dosing, patient education, and early monitoring were key to mitigating immune-related toxicities.
With appropriate counseling and protocols, outpatient administration is feasible, Dr. Diefenbach notes.
Regulatory Approval & Clinical Adoption
In November 2025, the U.S. FDA approved epcoritamab plus R² for adult patients with relapsed or refractory FL after at least one prior systemic therapy, marking the first bispecific antibody combination approved in this setting. This approval represents the earliest line in which a bispecific antibody has been incorporated into FL treatment.
Despite the robust efficacy and significant improvements in PFS observed with epcoritamab plus R², the long-term benefit of introducing a bispecific antibody earlier in the course of indolent follicular lymphoma is not yet established. Data are also limited for high-risk subgroups, including those with transformed disease or multiple prior lines of therapy, and the optimal sequencing after bispecific therapy including subsequent CAR T-cell therapy or retreatment strategies remains under investigation.
Additional considerations include cumulative toxicity, financial burden, and real-world feasibility, which will influence adoption in clinical practice.
Overall, the addition of epcoritamab to R² establishes a new benchmark in second-line follicular lymphoma, delivering unprecedented improvements in PFS and depth of response while maintaining a manageable outpatient safety profile. This chemotherapy-free regimen represents a paradigm shift toward earlier use of bispecific antibodies and is poised to redefine standards of care for appropriate patients with relapsed disease.
