Epcoritamab-bysp Approved for Relapsed/Refractory Follicular Lymphoma
Expert Perspectives · Lyn Brook · 2025-11-21
The FDA has approved epcoritamab-bysp (Epkinly®, Genmab US) in combination with lenalidomide and rituximab (R2) for adults with relapsed or refractory follicular lymphoma (FL). In addition, the FDA also converted the prior accelerated approval of epcoritamab-bysp monotherapy to traditional approval for adults with relapsed or refractory FL after two or more lines of systemic therapy.
Why This Approval Matters
Follicular lymphoma is a chronic, typically incurable B-cell non-Hodgkin lymphoma characterized by repeated relapses and decreasing response to therapy over time. Patients who relapse after R2 or multiple prior regimens have limited treatment options and are at risk for shortened progression-free intervals. The approval of epcoritamab-bysp plus R2 introduces a fixed-duration, subcutaneous T-cell–engaging regimen that demonstrated substantial improvements in progression-free survival (PFS) and overall response rate (ORR) compared with R2 alone, offering a new, active option earlier in the relapsed setting.
Breaking Down EPCORE FL-1
Efficacy and safety were evaluated in EPCORE FL-1 (Study M20-638; NCT05409066), a phase 3, randomized, open-label, multicenter trial in 488 adults with relapsed or refractory FL. Patients were randomized 1:1 to receive either epcoritamab-bysp plus R2 or R2 alone.
Patients had received a median of one prior line of systemic therapy; 24% had two prior lines and 17% had three or more prior lines, reflecting a population typical of early relapsed FL but including more heavily pretreated patients.
The primary end points were PFS and ORR as assessed by an independent review committee using Lugano 2014 Criteria. The epcoritamab-bysp arm demonstrated statistically significant results:
- PFS hazard ratio was 0.21, indicating a 79% relative reduction in the risk of progression or death
- Median PFS was not reached in those receiving epcoritamab-bysp plus R2 vs 11.2 months in those receiving R2 alone
- ORR was 89% with epcoritamab-bysp plus R2 versus 74% with R2 alone
Managing Adverse Events
The prescribing information for epcoritamab-bysp includes boxed warnings for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), consistent with other T-cell–redirecting therapies. Additional warnings and precautions address serious infections and cytopenias.
In EPCORE FL-1, serious adverse reactions occurred in 51% of patients receiving epcoritamab-bysp plus R2, including serious infections in 28%. CRS occurred in 24% of patients; serious CRS events were reported in 12%. ICANS occurred in 0.8% of patients.
Dosing and Administration
When used in combination with lenalidomide and rituximab, epcoritamab-bysp is administered subcutaneously for up to 12, 28-day cycles. Lenalidomide is given on Days 1 to 21 of each cycle, and rituximab is administered for five cycles.
The recommended epcoritamab-bysp dosage uses a three-step step-up schedule in Cycle 1 to mitigate CRS risk:
- Cycle 1: 0.16 mg on Day 1, 0.8 mg on Day 8, 3 mg on Day 15, then 48 mg on Day 22
- Cycles 2 and 3: 48 mg once weekly
- Cycles 4-12: 48 mg every 4 weeks