The FDA has granted approval for epcoritamab-bysp (Epkinly) in combination with rituximab and lenalidomide for treating adult patients with relapsed or refractory follicular lymphoma, marking the first bispecific antibody combination therapy available for this indication. The regulatory agency also converted epcoritamab's previous accelerated approval to full approval for monotherapy use in patients who have received at least two prior lines of therapy.
The combination approval was supported by results from the pivotal Phase 3 EPCORE FL-1 trial, which met both coprimary endpoints of overall response rate and progression-free survival. In a preplanned interim analysis involving 488 patients, the epcoritamab-based triplet regimen demonstrated a 79% reduction in the risk of disease progression or death compared to rituximab plus lenalidomide alone (HR, 0.21; 95% CI, 0.13-0.33; P < 0.0001).
Clinical Efficacy Results
The EPCORE FL-1 study showed compelling efficacy outcomes across multiple endpoints. The median progression-free survival was not reached in the epcoritamab arm (95% CI, 21.9 months-NR) compared to 11.2 months (95% CI, 10.5-NR) in the control arm. The overall response rate reached 89% (95% CI, 84%-93%) with the triplet combination versus 74% (95% CI, 68%-79%) with standard care alone (P < 0.0001).
Particularly notable was the complete response rate, with 74% of patients achieving complete response in the epcoritamab combination arm (n=181/243, 95% CI: 69%-80%, p<0.0001) compared to 43% in the control group (n=106/245, 95% CI: 37%-50%). According to Lorenzo Falchi, M.D., lymphoma specialist at Memorial Sloan Kettering Cancer Center, "The results shown with EPKINLY + R2 in the EPCORE FL-1 study are incredibly meaningful, demonstrating durable responses compared to patients treated with R2 alone."
Trial Design and Patient Population
EPCORE FL-1 was an open-label, randomized study evaluating subcutaneous epcoritamab in combination with rituximab and lenalidomide versus rituximab and lenalidomide alone in adult patients with relapsed or refractory follicular lymphoma. The study included a broad range of patients with indolent to aggressive disease.
Eligible patients required histologically confirmed classic, stage II to IV follicular lymphoma without evidence of histologic transformation that was relapsed or refractory to at least one prior systemic regimen containing an anti-CD20 monoclonal antibody in combination with chemotherapy. Patients were randomly assigned 1:1 to receive either epcoritamab at 48 mg subcutaneously for up to 12, 28-day cycles in combination with rituximab at 375 mg/m² for up to 5 cycles and lenalidomide at 20 mg for up to 12 cycles, or rituximab plus lenalidomide at the same doses and schedules.
Safety Profile
The safety profile of the epcoritamab-based combination was consistent with the established profiles of the individual agents, with no new safety signals observed. The most common adverse reactions (≥20%) in patients receiving the triplet combination included rash, upper respiratory tract infections, fatigue, injection site reactions, constipation, diarrhea, cytokine release syndrome, pneumonia, COVID-19, and fever.
Cytokine release syndrome occurred in 24% of patients at the recommended 3 step-up dosage schedule and was primarily low grade (19% Grade 1, 5% Grade 2). A single event of immune effector cell-associated neurotoxicity syndrome occurred in one patient (grade 1, 0.8%). The most common Grade 3 to 4 laboratory abnormalities (≥10%) were decreased neutrophil count, lymphocyte count, and platelets.
Clinical Significance and Future Directions
This approval addresses a significant unmet medical need in follicular lymphoma, which affects approximately 15,000 new patients per year in the United States. The disease is considered incurable with current available therapies, and patients often experience relapses with potential transformation to more aggressive forms of lymphoma.
"With this approval, EPKINLY is now the first bispecific antibody available for patients with follicular lymphoma in the second-line plus setting," stated Daejin Abidoye, MD, vice president and therapeutic area head of oncology at AbbVie. The combination had previously received Breakthrough Therapy Designation from the FDA for this indication.
Epcoritamab is an IgG1-bispecific antibody created using Genmab's proprietary DuoBody technology and administered subcutaneously. The drug is designed to simultaneously bind to CD3 on T cells and CD20 on B cells, inducing T-cell-mediated killing of CD20+ cells. Additional data from EPCORE FL-1 are planned to be presented at the 2025 ASH Annual Meeting, and both AbbVie and Genmab will pursue additional international regulatory approvals for this indication.
