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

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. Research Sponsor: This study was sponsored by Seagen, which was acquired by Pfizer in Dec. 2023.