Abstract 6239: Modeling and simulation of CRS events in low-risk populations with a rapid ramp-up SUD regimen of epcoritamab

Abstract Background: Epcoritamab is the only subcutaneous CD3xCD20 bispecific antibody approved for the treatment of adults with different types of relapsed or refractory (R/R) large B-cell lymphoma (LBCL) and R/R follicular lymphoma after ≥2 prior lines of systemic therapy. Cytokine release syndrome (CRS) is a known adverse event with T-cell engagers. A 2-step step-up dosing (SUD) in cycle 1 with CRS prophylaxis consisting of dexamethasone and fluids, involving a priming dose (0.16 mg on day 1) and an intermediate dose (0.8 mg on day 8) before the target dose (48 mg on day 15), has been identified as the optimal SUD for epcoritamab to reduce CRS risk in patients with diffuse LBCL (DLBCL). However, due to the aggressive disease and fast progression, patients with R/R DLBCL with a low risk of developing CRS may benefit from a shorter SUD regimen, allowing for quicker administration of the target dose without significantly increased CRS event rates following treatment. Methods: We performed model-based simulations for patients with R/R LBCL at lower risk of developing CRS (eg, patients who received prior CAR T therapy) utilizing a previously validated repeated time-to-event model which captures the time course and frequency of grade (G) ≥2 CRS under various SUD regimens. Specifically, we explored regimens that would shorten the 14-day period between the initial priming dose and the target full dose. For each simulated regimen, the predicted event rate of G≥2 CRS was assessed to determine the impact of the modified SUD. Results: The model was able to accurately predict CRS event risk: approximately 11% of GCT3013-01 DLBCL optimization cohort patients (9/81) had a G≥2 CRS event, with CRS prophylaxis consisting of dexamethasone and adequate hydration, and our model predicted a CRS event rate of ∼11%. Patients with prior CAR T therapy are predicted to have even lower CRS risk: ∼4% risk of a G≥2 CRS event under the current 2-step SUD regimen, and ∼5% risk of a G≥2 CRS event under a rapid ramp-up 1-week SUD (eg, priming on day 1, intermediate on day 4, and target dose on day 8). Despite the small increased risk of a CRS event with the rapid ramp-up SUD, the risk of an event is still lower than the observed G≥2 CRS event rate in the overall GCT3013-01 optimization cohort (ie, ∼11%). Conclusions: Shortening the SUD to 1 week in patients at low risk for CRS (eg, patients with prior CAR T) resulted in a similar G≥2 CRS rate compared with the current SUD regimen, as predicted by the model. Based on these simulations, a 1-week rapid ramp-up SUD may be beneficial in selected patients to deliver the target full dose of epcoritamab in a shorter time without undue risk. Further confirmation of this finding in clinical studies may be warranted. Citation Format: Matthew Putnins, Eric Song, Merzu Belete, Sri Sridhar, Han Si, Behnam Noorani, Mohamed-Eslam Mohamed, Manish Gupta, Mariana Sacchi, Steven Xu, Tommy Li. Modeling and simulation of CRS events in low-risk populations with a rapid ramp-up SUD regimen of epcoritamab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6239.