Background: Epcoritamab, a subcutaneous (SC) CD3xCD20 bispecific antibody, is approved by the US FDA for the treatment (tx) of adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic tx. CRS is inherent with the mechanism of action of T-cell engagers. For epcoritamab, CRS is mitigated by premedication, SC administration, and step-up dosing (SUD). The approved epcoritamab SUD for relapsed/refractory DLBCL during cycle 1 is SUD 1 of 0.16 mg on day (D) 1, SUD 2 of 0.8 mg on D8, and first full dose of 48 mg on D15. After tx delay, restarting SUD (ie, repriming) is needed to mitigate CRS risk. The aim of this study was to determine repriming windows using a model-based approach. Methods: Modeling and simulation identified repriming windows. For the pharmacokinetics (PK)-based approach, we assumed that prolonged dose delay may result in a drop in epcoritamab concentration and increased risk of CRS upon subsequent dosing. Safe repriming windows were determined using PK model–based simulations for epcoritamab concentrations above the trough concentration achieved at the end of the priming dose. The second approach leveraged a previously developed repeated time-to-event model to capture time course and frequency of grade (G) ≥2 CRS events. Risk of G≥2 events in different dosing delay scenarios was used to determine safe repriming windows based on the criteria that tx after dose delay should not lead to increased risk of G≥2 CRS vs regular schedule administration. Results: Using model-based simulations as a conservative upper bound, a repriming window of 8 d following SUD 1 was identified for delayed intermediate dose, which corresponds to the intermediate dose being delayed by 1 d. For delayed first full dose, the repriming window was 14 d (corresponding to the first full dose being delayed by 7 d). For delayed full dose following first full dose, the window was 6 weeks. The findings of this study agree with available clinical data in which dose delays shorter than model-predicted repriming windows did not increase CRS risk. Conclusion: Repriming windows were systematically and quantitatively selected and implemented in clinical studies. Findings are supported by clinical observations.
