Exposure-Response Analysis of Enfortumab Vedotin Plus Pembrolizumab as First-Line Therapy for Locally Advanced or Metastatic Urothelial Cancer.

Enfortumab vedotin is a nectin-4-directed antibody-drug conjugate currently approved in combination with pembrolizumab for the first-line treatment of locally advanced or metastatic urothelial cancer. Here we describe the exposure-response relationship between enfortumab vedotin exposures and efficacy/safety endpoints in patients who received ≥1 dose of enfortumab vedotin 1.25 mg/kg (on days 1 and 8 of a 21-day dosing cycle) plus pembrolizumab (recommended dosage) and had evaluable pharmacokinetics in the EV-103 (N = 121) and EV-302 (N = 432) studies. Overall, most patients were older (median age of 69 years), White (74%), and male (77%), with median body weight in EV-103 (79 kg) trending higher than that in EV-302 (75 kg). Higher exposures of enfortumab vedotin were associated with consistently higher objective response rates across all exposure quartiles in both studies, and longer survival than chemotherapy in EV-302. Increased and faster incidence of treatment-related adverse events (Grade ≥ 3 hyperglycemia, Grade ≥ 3 skin reactions, and Grade ≥ 2 peripheral neuropathy) was also observed with increased exposures. However, dose modifications were effective in managing most adverse events, with most patients having at least partial resolution (hyperglycemia, >75%; skin reactions, >85%; and peripheral neuropathy, >50%). Responses attained with higher early cycle exposure were not impacted by subsequent dose modifications. Overall, exposure-response analysis supports the use of enfortumab vedotin at a starting dose of 1.25 mg/kg and in combination with pembrolizumab for first-line treatment of locally advanced or metastatic urothelial cancer.