Population Pharmacokinetic Modeling and Exposure-Response Analysis for the Antibody-Drug Conjugate Enfortumab Vedotin in Locally Advanced or Metastatic Urothelial Carcinoma.

Enfortumab vedotin is a fully human monoclonal antibody directed to Nectin-4 and conjugated to monomethyl auristatin E (MMAE), approved for treatment of previously treated locally advanced or metastatic urothelial carcinoma (mUC). This population analysis characterized pharmacokinetics of enfortumab vedotin and free (unconjugated) MMAE, identified covariates affecting pharmacokinetics, and evaluated weight-based dosing for enfortumab vedotin. Exposure-response analyses characterized relationships between enfortumab vedotin and free MMAE exposures and efficacy/safety endpoints. Data from 748 patients with locally advanced or mUC in 5 clinical studies were analyzed using nonlinear mixed-effects modeling. Patients received enfortumab vedotin 0.50-1.25 mg/kg every 3 weeks or on days 1, 8, and 15 of a 28-day cycle. Relevant covariates retained in final models were evaluated for clinical relevance to enfortumab vedotin and free MMAE exposures. Although some covariates produced differences in exposure, the magnitude of changes was not clinically meaningful. Simulations indicated weight-based dosing yielded more consistent exposures across body weight groups vs. a hypothetical fixed-dose regimen of enfortumab vedotin 95 mg (calculated for median body weight, 75 kg). Exposure-response analysis showed average enfortumab vedotin concentrations were not a statistically significant predictor of overall survival (hazard ratio 0.91, 95% confidence interval: 0.72-1.14; P = 0.41); all exposure quartiles had a greater median overall survival than chemotherapy (11.0-12.6 vs. 9.0 months). Enfortumab vedotin and free MMAE exposures were statistically significant predictors of grade ≥ 3 treatment-related adverse events (both P < 0.0001). This analysis supports enfortumab vedotin 1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle.