Clinical pharmacology of the antibody-drug conjugate enfortumab vedotin in advanced urothelial carcinoma and other malignant solid tumors.
Authors: Tang Mei , Garg Amit , Bonate Peter , Rosenberg Jonathan E. , Kadokura Takeshi , Yamada Akihiro , Fukushi Risa , Koibuchi Akira , Hanley William D. , Poondru Srinivasu 
Published: February 2022

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Background: Enfortumab vedotin (EV) is an antibody-drug conjugate comprised of a fully human monoclonal antibody directed against Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. EV is approved in the US for treatment of adult patients (pts) with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received a PD-1/L1 inhibitor and platinum-based chemotherapy, and who are ineligible for cisplatin-based chemotherapy and previously received 1+ lines of therapy. In EV-301, EV significantly reduced risk of death by 30% vs chemotherapy in pts with treated la/mUC. Data from five clinical studies (N = 748) were used to describe the clinical pharmacology of EV. Methods: Pharmacokinetics (PK) of EV and free MMAE were studied in pts with la/mUC (n = 699) and malignant solid tumors receiving EV in phase 1, 2, and 3 studies. EV and MMAE PK parameters were calculated with non-compartmental analysis. Population PK analysis was used to characterize/assess impact of covariates on EV and MMAE PK. Antitherapeutic antibodies (ATA) were assessed in all studies. Results: EV 0.5 to 1.25 mg/kg IV on Days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. Mean EV and MMAE clearance was 0.110 and 2.11 L/h, respectively; elimination t1/2 was 3.6 and 2.6 days. Steady state was reached by Cycle 1; accumulation was limited for EV and MMAE between cycles. EV PK differences in special populations were not considered clinically meaningful. For renal impairment, no significant differences in exposure of EV and MMAE were observed in mild (n = 272), moderate (n = 315), or severe (n = 25) impairment vs normal renal function. For hepatic impairment, bilirubin was a significant covariate for MMAE only; pts with mild impairment (n = 65) had a 37% increase in AUC0-28d and 31% increase in Cmax of MMAE vs pts with normal hepatic function. No clinically significant differences in EV and MMAE PK were observed based on age (range, 24-90 yrs; > 65 yrs, 60%), sex (male, 73%), or race/ethnicity (White, 69%; Asian, 21%; Black, 1%; others/unknown, 8%). Weight-based dosing showed similar exposure for all pts. EV did not prolong mean QTc interval to a clinically relevant extent per ECG/PK data from the EV-102 study (n = 17; advanced UC). Concomitant use with dual P-gp and strong CYP3A4 inhibitors may increase MMAE exposure and may increase the risk of adverse events. Following EV 1.25 mg/kg, 16/590 (2.7%) pts tested positive for ATA against EV at ≥1 postbaseline time point. Conclusions: Integration of EV and free MMAE PK findings support the EV dose of 1.25 mg/kg on Days 1, 8, and 15 of a 28-day cycle. No dose adjustments were required for special populations or by age, sex, or race. Caution is advised during concomitant treatment with strong CYP3A4 inhibitors, and a low rate of immunogenicity was observed.