Impact of exposure on outcomes with enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer.

4503 Background: Enfortumab vedotin (EV) is approved in combination with pembrolizumab and as a monotherapy for locally advanced or metastatic urothelial cancer (la/mUC). EV, alone and in combination with pembrolizumab, has demonstrated an OS benefit and a generally manageable safety profile in patients (pts) with previously treated or untreated la/mUC. Dose modifications, including reductions and interruptions, are recommended to manage EV-related AEs. This analysis evaluates the association between EV plasma exposure, which is impacted by dose modifications, and safety and efficacy outcomes. Methods: Characterization of dose- and exposure-response for efficacy and exposure-response for safety outcomes included pts in EV-101 (EV monotherapy 0. 75, 1. 0, and 1. 25 mg/kg on days 1, 8, and 15 of a 28-day cycle 3Q4W), EV-201, and EV-301 (EV monotherapy 1. 25 mg/kg 3Q4W). Time-averaged exposure up to an event of interest, C avg, was computed using a population PK model. PK assessment included multiple samples in first 2 cycles, and pre-dose samples in subsequent cycles. Results: Dose modifications were common, including dose reductions to 1. 0 mg/kg (EV-201 42. 1%; EV-301 35. 1%) and 0. 75 mg/kg (EV-201 13. 6%; EV-301 11. 1%). EV showed consistent improvement in median PFS and OS vs chemotherapy across all exposure quartiles in EV-301 inclusive of dose modifications (Table). Greater initial EV exposure in the first 2 cycles was associated with a higher ORR and was consistent with dose-response (0. 75 mg/kg 21. 4% sample size n = 14; 1. 0 mg/kg 18. 5% n = 27; 1. 25 mg/kg 40-51. 1% across studies n = 613). Lower EV exposure was associated with lower risk of EV-related Grade ≥3 rash or skin reactions, Grade ≥2 peripheral neuropathy, and Grade ≥3 hyperglycemia (P<0. 0001 for all). Conclusions: EV improved PFS and OS outcomes vs chemotherapy in pts with la/mUC across all exposure quartiles. The starting dose of 1. 25 mg/kg 3Q4W resulted in EV exposure that maximized likelihood of response. Recommended dose modifications are effective for managing EV-related AEs and should be used as clinically indicated. Clinical trial information: NCT02091999, NCT03219333, and NCT03474107. Table: see text