12.1 Mechanism of Action

Enfortumab vedotin-ejfv is an ADC. The antibody is a human IgG1 kappa directed against Nectin-4, an adhesion protein located on the surface of cells. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Nonclinical data suggest that the anticancer activity of enfortumab vedotin-ejfv is due to the binding of the ADC to Nectin-4-expressing cells, followed by internalization of the ADC-Nectin-4 complex, and the release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis. The combination of enfortumab vedotin-ejfv with a PD-1 blocking antibody resulted in up-regulation of immune function and increased anti-tumor activity in syngeneic mouse tumor models expressing Nectin-4.

12.2 Pharmacodynamics

In an exposure-response analysis for safety, higher enfortumab vedotin-ejfv exposure was associated with higher incidence of some adverse reactions (e.g., Grade ≥2 peripheral neuropathy, Grade ≥3 hyperglycemia). The exposure‑response relationship for efficacy has not been fully characterized.

Cardiac Electrophysiology

At the recommended dose, PADCEV had no large QTc prolongation (>20 msec).

12.3 Pharmacokinetics

Enfortumab vedotin-ejfv (ADC) pharmacokinetics were characterized after single and multiple doses in patients with solid tumors.

The pharmacokinetics of the ADC and unconjugated MMAE were consistent when assessed following PADCEV administration as a single agent and in combination with intravenous pembrolizumab after 1 treatment cycle.

The exposure parameters of the ADC and unconjugated MMAE (the cytotoxic component of enfortumab vedotin-ejfv) are summarized in Table 19 below. Peak ADC concentrations were observed near the end of intravenous infusion while peak unconjugated MMAE concentrations were observed approximately 2 days after PADCEV dosing. Minimal accumulation of the ADC and unconjugated MMAE was observed following repeat administration of PADCEV in patients. Steady-state concentrations of the ADC were reached after 1 treatment cycle for the ADC as a single agent and in combination with intravenous pembrolizumab.

Distribution

The estimated mean steady-state volume of distribution of the ADC was 12.8 L following administration of PADCEV. In vitro, plasma protein binding of unconjugated MMAE ranged from 68% to 82%.

Elimination

The ADC and unconjugated MMAE exhibited multi-exponential declines with an elimination half-life of 3.6 days and 2.6 days, respectively. The mean clearance (CL) of the ADC and unconjugated MMAE was 0.11 L/h and 2.11 L/h, respectively. Elimination of unconjugated MMAE appeared to be limited by its rate of release from the ADC.

Metabolism

Catabolism of the ADC has not been studied in humans; however, it is expected to undergo catabolism to small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. The ADC releases MMAE via proteolytic cleavage, and unconjugated MMAE is primarily metabolized by CYP3A4 in vitro.

Excretion

The excretion of the ADC is not fully characterized. Following a single-dose of another ADC that contains unconjugated MMAE, 17% of the total unconjugated MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged form. A similar excretion profile of unconjugated MMAE is expected after PADCEV administration.

Specific Populations

No clinically significant differences in the pharmacokinetics of the ADC or unconjugated MMAE were identified based on age (24 to 90 years), sex, race (White, Asian, or Black), renal impairment, and mild hepatic impairment (total bilirubin of 1 to 1.5 × ULN and any AST, or total bilirubin ≤ULN and AST >ULN). The effect of end-stage renal disease with or without dialysis and moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) on the pharmacokinetics of the ADC or unconjugated MMAE is unknown.

Drug Interaction Trials

No clinical trials evaluating the drug-drug interaction potential of the ADC have been conducted.

Physiologically Based Pharmacokinetic (PBPK) Modeling Predictions:

Dual P-gp and Strong CYP3A4 Inhibitor: Concomitant use of PADCEV with ketoconazole (a dual P-gp and strong CYP3A4 inhibitor) is predicted to increase unconjugated MMAE Cmax by 15% and AUC by 38%.

Dual P-gp and Strong CYP3A4 Inducer: Concomitant use of PADCEV with rifampin (a dual P-gp and strong CYP3A4 inducer) is predicted to decrease unconjugated MMAE Cmax by 28% and AUC by 53%.

Sensitive CYP3A Substrates: Concomitant use of PADCEV is predicted not to affect exposure to midazolam (a sensitive CYP3A substrate).

In Vitro Studies

Transporter Systems: MMAE is a substrate of P-glycoprotein (P-gp) and is not an inhibitor of P-gp.

12.6 Immunogenicity

The observed incidence of anti-drug antibody (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of PADCEV or of other enfortumab vedotin products.

ADA was evaluated during the treatment periods (up to 5.5 years) in nine clinical studies of PADCEV as a single agent or in combination with intravenous pembrolizumab at the approved recommended dosages. Anti‑enfortumab vedotin-ejfv antibodies developed in:

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3.7% (25/684) of patients who received PADCEV as a single agent.

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1.3% (2/156) of patients who received PADCEV in combination with intravenous pembrolizumab for the treatment of MIBC.

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7% (34/485) of patients who received PADCEV in combination with intravenous pembrolizumab for the treatment of la/mUC.

Because of the low occurrence of ADA, the effect of the ADA on the pharmacokinetics, pharmacodynamics, safety, and/or effectiveness of PADCEV is unknown.