Epcoritamab Step-Up Dosing Regimen Selection and Optimization Using Repeated Time-to-Event Modeling for Cytokine Release Syndrome Risk Mitigation.

Epcoritamab is a CD3 × CD20 T-cell-engaging bispecific antibody approved for the treatment of various types of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) and R/R follicular lymphoma (FL), after at least two lines of systemic therapy. Here, we develop and calibrate repeated time-to-event models to assess the impact of optimized step-up dosing (SUD) regimens and the effect of intravenous fluids and/or corticosteroids on cytokine release syndrome (CRS) risk. The analysis used pooled data from 600 patients with aggressive non-Hodgkin lymphoma (aNHL) and indolent NHL (iNHL) who received subcutaneous epcoritamab in 28-day cycles in the EPCORE® NHL-1 and EPCORE® NHL-3 studies (NCT03625037, NCT04542824). In the calibrated model, prior CAR T cell therapy (125/600 patients [20.8%]) was associated with a 69.7% reduction (95% confidence interval [CI], 38.2-85.2) in the maximum stimulatory effect of epcoritamab on the hazard of Grade ≥2 CRS. Intravenous fluids or dexamethasone during Cycle (C)1 were associated with a 2.89-fold (95% CI, 1.57-5.30) increase in the half-maximal effective plasma concentration of epcoritamab on stimulation (S50). Furthermore, prophylaxis with intravenous fluids and dexamethasone during C1 was associated with a 3.79-fold (95% CI, 1.65-8.73) increase in S50. Simulations show that the use of dexamethasone further reduces Grade ≥2 CRS risk compared with prednisone in patients with aNHL/iNHL. Moreover, a 3-SUD design further reduces CRS risk in patients with iNHL. Overall, our models showed that the approved 2-SUD regimen for R/R LBCL and 3-SUD regimen for R/R FL-together with intravenous fluids and dexamethasone prophylaxis-are adequate to reduce Grade ≥2 CRS risk.