Evaluating the Impact of Enfortumab Vedotin Dose Modifications on Clinical Efficacy Using Tumor Growth Inhibition Modeling in Patients With Advanced Urothelial Cancer

Enfortumab vedotin (EV) is approved for previously treated locally advanced or metastatic urothelial cancer (mUC), based on results from pivotal trials (phase 2, EV-201; phase 3, EV-301) evaluating EV monotherapy at 1.25 mg/kg 3Q4W (Days 1, 8, and 15 of a 28-day cycle). Adverse events (AEs) were managed by protocol-recommended dose modifications, with 35.5%-51.7% patients requiring dose reductions and most patients in EV-301 maintaining the 1.25 mg/kg dose through Cycle 7. Dose modifications appeared to have a limited impact on long-term efficacy in patients who achieved a response. Given that target lesion shrinkage is predictive of progression-free survival (PFS) and overall survival (OS) in patients with mUC in EV-301, we aimed to quantify the impact of EV starting dose and dose modifications on response onset and durability, hence the impact on PFS and OS, by characterizing tumor dynamics via a tumor growth inhibition (TGI) model. A population pharmacokinetic-TGI model was developed using data from 603 patients with mUC who received EV monotherapy at 0.5-1.25 mg/kg 3Q4W. Various dosing simulations indicated that a 1.25 mg/kg starting dose maximized the likelihood of response, and dose modifications at or after Cycle 3 had limited impact on simulated response duration. However, unwarranted treatment modifications in earlier treatment cycles (