PADCEV EJFV Powder for solution for injection Ref.[10213] Active ingredients: Enfortumab vedotin

In an exposure-response analysis, higher enfortumab vedotin exposure was associated with higher incidence of some adverse reactions (e.g., Grade ≥2 peripheral neuropathy, Grade ≥3 hyperglycemia) and a lower exposure was associated with lower efficacy.

Cardiac Electrophysiology

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

Population pharmacokinetic analysis included data from 369 patients based on three Phase 1 studies and one Phase 2 study. Enfortumab vedotin-ejfv pharmacokinetics were characterized after single and multiple doses in patients with locally advanced or metastatic urothelial carcinoma and other solid tumors.

The exposure parameters of ADC and unconjugated MMAE (the cytotoxic component of enfortumab vedotin-ejfv) are summarized in Table 5 below. Peak ADC concentrations were observed near the end of intravenous infusion while peak MMAE concentrations were observed approximately 2 days after enfortumab vedotin-ejfv dosing. Minimal accumulation of the ADC and MMAE was observed following repeat administration of enfortumab vedotin-ejfv in patients. Steady-state concentrations of ADC and MMAE were reached after 1 treatment cycle.

Table 5. Exposure parameters of ADC and unconjugated MMAE after first treatment cycle of 1.25 mg/kg of enfortumab vedotin-ejfv dose of Days 1, 8 and 15:

C_max = maximum concentration, AUC_0-28d = area under the concentration-time curve from time zero to 28 days, C_trough,0-28d = pre-dose concentration on day 28

Distribution

The estimated mean steady-state volume of distribution of ADC was 11 liters following administration of enfortumab vedotin-ejfv. Plasma protein binding of MMAE ranged from 68% to 82%, in vitro.

Elimination

ADC and MMAE exhibited multi-exponential declines with an elimination half-life of 3.4 days and 2.4 days, respectively. The mean clearance (CL) of enfortumab vedotin-ejfv and free MMAE in patients was 0.10 L/h and 2.7 L/h, respectively, in patients. Elimination of MMAE appeared to be limited by its rate of release from enfortumab vedotin-ejfv.

Metabolism

Enfortumab vedotin-ejfv catabolism 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. Enfortumab vedotin-ejfv releases MMAE via proteolytic cleavage, and MMAE is primarily metabolized by CYP3A4 in vitro.

Excretion

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

Specific Populations

Based on population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of enfortumab vedotin-ejfv were observed based on age (24 to 87 years), sex, or race/ethnicity (Caucasian, Asian, Black, or others).

Hepatic Impairment

Based on population pharmacokinetics analysis, there was a 48% AUC increase in unconjugated MMAE exposure observed in patients with mild hepatic impairment (bilirubin of 1 to 1.5 × ULN and AST <ULN, or bilirubin ≤ULN and AST >ULN, n=31) compared to normal hepatic function. The effect of moderate or severe hepatic impairment (AST or ALT >2.5 x ULN or total bilirubin >1.5 x ULN) or liver transplantation on the pharmacokinetics of ADC or unconjugated MMAE is unknown.

Renal Impairment

The pharmacokinetics of enfortumab vedotin-ejfv and MMAE were evaluated after the administration of 1.25 mg/kg of enfortumab vedotin-ejfv to patients with mild (creatinine clearance; CrCL >60–90 mL/min; n=135), moderate (CrCL 30–60 mL/min; n=147) and severe (CrCL <30 mL/min; n=8) renal impairment. No significant differences in exposure (AUC) of ADC and MMAE were observed in patients with mild, moderate or severe renal impairment compared to patients with normal renal function. The effect of end stage renal disease with or without dialysis on the pharmacokinetics of ADC or unconjugated MMAE is unknown.

Drug Interaction Studies

Clinical Studies

No clinical studies evaluating the drug-drug interaction potential of enfortumab vedotin-ejfv have been conducted. To characterize the drug-drug interaction potential of free MMAE, clinical studies with another ADC that contains MMAE are described below.

Strong CYP3A4 Inhibitors: Another ADC that contains MMAE co-administered with ketoconazole (a strong CYP3A4 inhibitor) increased MMAE C_max by 25% and AUC by 34%, with no change in ADC exposure. The concomitant use of strong inhibitors of CYP3A4 with PADCEV would likely result in similar effects on free MMAE and ADC.

Strong CYP3A4 Inducers: Another ADC that contains MMAE co-administered with rifampin (a strong CYP3A4 inducer) decreased MMAE C_max by 44% and AUC by 46%, with no change in ADC exposure. The concomitant use of strong inducers of CYP3A4 with PADCEV would likely result in similar effects on free MMAE and ADC.

Sensitive CYP3A4 Substrates: Another ADC that contains MMAE co-administered with midazolam (a sensitive CYP3A4 substrate) did not affect the exposure of midazolam. Similarly, PADCEV is not expected to alter the exposure of drugs that are metabolized by CYP3A4 enzymes.

In Vitro Studies

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

Carcinogenicity studies with enfortumab vedotin-ejfv or the small molecule cytotoxic agent (MMAE) have not been conducted.

MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism. This effect is consistent with the pharmacological effect of MMAE as a microtubule-disrupting agent. MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.

Fertility studies with enfortumab vedotin-ejfv or MMAE have not been conducted. However, results of repeat-dose toxicity studies in rats indicate the potential for enfortumab vedotin-ejfv to impair male reproductive function and fertility.

In repeat-dose toxicology studies conducted in rats for up to 13 weeks, doses ≥2 mg/kg enfortumab vedotin-ejfv (at exposures similar to the exposures at the recommended human dose) resulted in decreases in testes and epididymis weights, seminiferous tubule degeneration, spermatid/spermatocyte depletion in the testes and cell debris, sperm granuloma and hypospermia/abnormal spermatids in the epididymis. Findings in the testes and epididymis did not reverse by the end of the recovery period.

14.1 Metastatic Urothelial Cancer

The efficacy of PADCEV was evaluated in EV-201 (NCT03219333), single-arm, multicenter trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. Patients were excluded if they had active CNS metastases, ongoing sensory or motor neuropathy ≥ Grade 2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥8% or HbA1c ≥7% with associated diabetes symptoms.

The median age was 69 years (range: 40 to 84 years), 70% were male, and 85% were Caucasian. All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (32%) or 1 (68%). Ninety percent of patients had visceral metastases including 40% with liver metastases. Two-thirds of patients had pure transitional cell carcinoma (TCC) histology; 33% had TCC with other histologic variants. An immunohistochemistry clinical trial assay was used to assess patients with tumor tissue available, and detected Nectin-4 expression in all patients tested (n=120). The median number of prior systemic therapies was 3 (range: 1 to 6). Forty-six percent of patients received prior PD-1 inhibitor, 42% received prior PD-L1 inhibitor, and an additional 13% received both PD-1 and PD-L1 inhibitors. Sixty-six percent of patients received prior cisplatin-based regimens, 26% received prior carboplatin-based regimens, and an additional 8% received both cisplatin and carboplatin-based regimens.

The major efficacy outcome measures were confirmed objective response rate (ORR) and duration of response (DOR) assessed by blinded independent central review (BICR) using RECIST v1.1.

Efficacy results are presented in Table 6.

Table 6. Efficacy Results in EV201 (BICR Assessment):

NE = not estimable
* Median follow-up duration of 10.2 months
^† Kaplan-Meier estimate
^‡ Based on patients (n=55) with a response by BIC