Clinical Summary:

• Design/Population: The phase 3 EPCORE FL-1 trial randomized patients with CD20-posiive follicular lymphoma who received prior systemic therapy to receive fixed-duration epcoritamab plus lenalidomide and rituximab or lenalidomide plus rituximab alone. Dual primary end points were objective response and progression-free survival (PFS). 
• Key Outcomes: Epcoritamab plus lenalidomide and rituximab significantly improved response and PFS, reducing the risk of disease progression or death by 79%. Grade 3/4 neutropenia and infections were more frequent with epcoritamab plus lenalidomide and rituximab, while cytokine release syndrome was low grade with the 3-step-up dosing schedule.
• Clinical Relevance: The magnitude of PFS and response improvement supports epcoritamab plus lenalidomide and rituximab as a potentially practice-changing, fixed-duration treatment strategy for second-line or later follicular lymphoma, although increased rates of severe neutropenia and infections remain important considerations when selecting and monitoring patients. 

Results from the phase 3 EPCORE FL-1 trial demonstrated that epcoritamab plus lenalidomide and rituximab significantly improved response and progression-free survival (PFS) compared with lenalidomide and rituximab alone in patients with relapsed or refractory follicular lymphoma. 

These results were presented by Bradley Hunter, MD, Intermountain LDS Hospital, Salt Lake City, Utah, at the at the Society of Hematologic Oncology (SOHO) Annual Meeting in Houston, Texas.

In this study, 488 adult patients with CD20-positive follicular lymphoma whose disease had relapsed or was refractory following at least 1 prior line of therapy were randomized to receive either epcortiamb plus lenalidomide and rituximab (n = 243) or lenalidomide and rituximab alone (n = 245) for up to 12 cycles. 

Epcoritamab was administered subcutaneously with a 2- or 3-step-up dosing schedule to a target dose of 48 mg during cycle 1. Treatment was administered weekly during cycles 1 through 3 and every 4 weeks during cycles 4 to 12. Lenalidomide was administered during days 1 through 21 of cycles 1 through 12, while intravenous rituximab was administered weekly during cycle 1 and every 4 weeks during cycles 2 through 5. Cytokine release syndrome prophylaxis was mandatory during cycle 1.

The dual primary end points were objective response rate (ORR) and PFS. Key secondary end points included complete response rate, overall survival (OS), duration of response, duration of complete response, and safety.

At a median follow-up of 14.8 months, ORR was 95% with epcoritamab plus lenalidomide and rituximab and 79% with lenalidomide plus rituximab (P < .0001). Complete response rate was also significantly higher in the epcoritamab-containing arm (83% vs 50%; P < .0001). 

Responses appeared more durable with epcoritamab plus lenalidomide and rituximab. The 12-month duration of response was 89.2% in the epcoritamab-containing arm and 48.5% in the lenalidomide plus rituximab arm. 

Epcoritamab plus lenalidomide and rituximab also significantly improved PFS, reducing the risk of disease progression or death by 79% compared with lenalidomide plus rituximab alone (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.14 to 0.31; P < .001), meeting the second dual primary end point. 

Cytokine release syndrome occurred in 26% of patients receiving epcoritamab plus lenalidomide and rituximab with the 3-step-up dosing schedule. Events occurred mostly after the first 48-mg epcoritamab dose and were grade 1 in 21% and grade 2 in 5%.

Treatment-emergent adverse events were more frequently reported in the epcoritamab-containing arm. Grade 3/4 treatment-emergent adverse events occurred in 90% of patients in the epcoritamab plus lenalidomide and rituximab arm and 67% of patients in the lenalidomide plus rituximab arm. The most frequently reported grade 3/4 adverse events included neutropenia (69% vs 42%), infections (33% vs 15%), and febrile neutropenia (6% vs 3%). 

Among patients receiving epcoritamab using the 3-step-up dosing schedule, cytokine release syndrome occurred in 26% of patients, including grade 1 cytokine release syndrome in 21% of patients and grade 2 cytokine release syndrome in 5% of patients. Most events occurred follwoign the first 48 mg dose and all events resolved. No grade ≥3 events were reported with this dosing schedule. 

Treatment-emergent adverse events led to discontinuation in 19% of patients receiving epcoritamab plus lenalidomide and rituximab and 12% of patients in the lenalidomide plus rituximab arm. Fatal treatment-emergent adverse events occurred in 2% of patients in the epcoritamab-containing arm and 4% of patients in the lenalidomide plus rituximab arm; none of the fatal events were considered related to epcoritamab.

The findings demonstrate that adding epcoritamab to lenalidomide and rituximab can substantially improve response depth, response durability, and disease control in relapsed or refractory follicular lymphoma. The fixed-duration regimen and subcutaneous administration may also support outpatient treatment, although the higher incidence of grade 3/4 neutropenia and infections with the combination requires appropriate monitoring and management.

Source:

Hunter BD, Falchi L, Nijland M, et al. Phase 3 results from the EPCORE FL-1 trial of epcoritamab with lenalidomide and rituximab vs lenalidomide and rituximab for relapsed or refractory follicular lymphoma: Phase 2 final results. Presented at the SOHO Annual Meeting; September 9-12, 2026; Houston, Texas. Abstract IBCL-1332.