Optimal dose regimen of epcoritamab in combination with lenalidomide and rituximab in relapsed or refractory follicular lymphoma - analyses of pharmacokinetics and exposure-response relationships of epcore FL-1 Phase 3 study Free

Introduction: Epcoritamab is a subcutaneous CD3xCD20 bispecific T-cell engager approved for treating relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and R/R follicular lymphoma (FL) after two or more lines of systemic therapy. Epcoritamab in combination with rituximab and lenalidomide (R²) is currently being evaluated for clinical benefit in patients with R/R FL who have received at least 1 prior line of systemic therapy (including an anti-CD20 antibody). Here, we present epcoritamab pharmacokinetics (PK) as well as exposure-response (E-R) results and justification for its dosing regimen in combination with R² from the EPCORE FL-1 study, an open-label, randomized, global Phase 3 trial evaluating the safety and efficacy of epcoritamab plus R² compared to R² alone in patients with R/R FL.

Methods: Two investigational arms were explored: epcoritamab 48 mg in combination with R² (Arm A, n=243) and epcoritamab 24 mg in combination with R² (Arm B, n=61). Initially, a 2-step up dosing (SUD) regimen was introduced for both arms, starting with a priming dose of 0.16 mg on Cycle 1, Day 1 (C1D1), followed by an intermediate dose of 0.8 mg on C1D8, and a full dose on C1D15 and beyond. However, based on data from the ongoing Phase 1/2 study EPCORE NHL-1, a 3 step-up SUD regimen was introduced for Arm A by adding a second intermediate dose of 3 mg on C1D15 to mitigate the risk of cytokine release syndrome (CRS). Epcoritamab full dose was administered once a week (QW) for either two or three cycles, and then every 4 weeks (Q4W) until Cycle 12. To identify the optimal epcoritamab dosing regimen in combination with R², comprehensive analyses of clinical safety, efficacy, PK, and pharmacodynamic data (including exposure-efficacy and exposure-safety analyses) were conducted across the 24 mg and 48 mg doses.

Results: Population PK (PopPK) analyses were conducted leveraging an established model for epcoritamab (Li et al. 2025 Clin Pharmacokinet). The PK of epcoritamab in combination with R² in patients with R/R FL was consistent with prior monotherapy assessments in R/R FL. Across the full doses studied (24 mg and 48 mg) in patients with R/R FL, a clear and statistically significant E-R trend was observed for time to event endpoints including duration of response (DOR), duration of complete response (DOCR), progression-free survival (PFS), and overall survival (OS). Overall, the higher epcoritamab exposure (approximately equivalent to the median for 48 mg exposure) was associated with improved outcomes compared to lower exposure (approximately equivalent to the median for 24 mg exposure). This suggests that the exposure associated with the 48 mg full dose of epcoritamab resulted in deeper and more durable responses than the lower exposure associated with the 24 mg full dose in patients with R/R FL. No E-R relationships were observed between steady-state C_trough at Q4W intervals and clinical responses, supporting the Q4W dosing after Cycle 3. Exposure-safety analyses did not show any significant trends for increases in adverse events (AEs) with increasing epcoritamab exposure, including Grade ≥3 treatment-emergent adverse events (TEAE), Grade ≥3 neutropenia, and Grade ≥3 infections. Moreover, the 3-step SUD regimen (0.16/0.8/3/48 mg full dose) along with hydration and dexamethasone prophylaxis during Cycle 1 reduced the risk of CRS compared to the 2-step regimen (0.16/0.8/48 mg full dose). No E-R relationship was observed for any grade or Grade ≥2 CRS. Interleukin (IL)-6 levels were lower 24 hours after the first full dose with the 3-step SUD regimen compared to the 2-step SUD regimen and these observations were consistent with the lower CRS rate observed in patients who received the 3-step vs. 2-step SUD regimen.Conclusions: FromPK and E-R analyses, the proposed full dose of 48 mg epcoritamab in combination with R² and its QW dosing during Cycles 1-3 followed by Q4W dosing during Cycles 4-12 is optimal for patients with R/R FL. This dosing regimen demonstrates tolerable safety profile and superior efficacy compared to the 24 mg full dose. The addition of a second intermediate dose of 3 mg (0.16/0.8/3/48 mg full dose regimen), along with hydration and dexamethasone prophylaxis during Cycle 1, significantly reduced cytokine release as well as CRS frequency and severity, supporting the proposed 3 step-up SUD dosing regimen in R/R FL.