Enfortumab vedotin

Enfortumab Vedotin is an antibody-drug conjugate directed against the receptor protein Nectin4 for the treatment of advanced or metastatic urothelial carcinoma. The antibody-drug conjugate is conjugated with the anti-microtubule drug monomethylauristatin E. As soon as the antibody binds to the Nectin4-expressing cell, the conjugate is internalized and the chemotherapeutic agent is released.

Enfortumab Vedotin (EV) consists of a fully human monoclonal antibody directed against Nectin4. Nectin4 is overexpressed in a number of cancers (especially urothelial carcinoma, ulcerative colitis and breast cancer - see also NECTIN4 gene). NECTIN4 amplifications are frequent genomic events, especially in muscle-invasive bladder cancer (TCGA bladder cancer). >90 % of patients with NECTIN4 amplifications showed objective responses to EV. In multivariable Cox analysis, adjusted for age, sex and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < 0.001) (Klümper N et al. 2024; Eckstein M 2025).

The EV antibody binds with high affinity and specificity to Nectin-4-expressing cells, preventing cross-reactivity with other Nectin-expressing cells. Once bound EV is internalized, this leads to the intracellular release of the microtubule-disrupting agent monomethylauristatin E (MMAE), which ultimately leads to apoptosis of the tumor cell.

In vitro, the binding of MMAE to human plasma proteins ranged from 68% to 82%. It is unlikely that MMAE displaces or is displaced by strongly protein-bound drugs. In vitro studies indicate that MMAE is a substrate of P-glycoprotein. A small portion of the MMAE released from enfortumab vedotin is metabolized. In vitro data indicate that the metabolism of MMAE occurs mainly via oxidation by CYP3A4 .

The mean clearance of ADC and unconjugated MMAE in patients was 0.11 l/h and 2.11 l/h, respectively. The elimination of MMAE appeared to be limited by its release rate from enfortumab vedotin. MMAE elimination showed a multi-exponential decline with a half-life of 2.6 days. The excretion of MMAE occurs mainly in the feces and to a lesser extent in the urine. After a single dose of another ADC containing MMAE, approximately 24% of the total MMAE administered was recovered in feces and urine as unchanged MMAE over a period of one week

Enfortumab vedotin (^Padcev®) is used as monotherapy for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have previously received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor. Enfortumab vedotin is intended for intravenous use. The recommended dose must be administered as an intravenous infusion over 30 minutes.

The use of enfortumab vedotin is not recommended during pregnancy and in women of childbearing age who are not using an effective contraceptive method, as enfortumab vedotin may damage the fetus. Embryo-fetal development studies in female rats have shown that intravenous administration of enfortumab vedotin resulted in a reduced number of viable fetuses, reduced litter size and increased early resorptions.

The most common side effects with enfortumab vedotin were:

• Alopecia (48.8%)
• fatigue (46.8%)
• decreased appetite (44.9%)
• peripheral sensory neuropathy (38.7%)
• diarrhea (37.6%)
• pruritus (33.4%)
• taste disturbances (29.9%)
• anemia (26.5%)
• Decreased weight (23.4%)
• maculopapular exanthema (22.9%)
• dry skin (21.6%)
• vomiting (18.4%)
• Increased aspartate aminotransferase (15.3%)
• Hyperglycemia (13.1%)
• Dry eyes (12.8%)
• increased alanine aminotransferase (12.1%)

The most common side effects were:

• diarrhea (2%) and
• hyperglycemia (2%).

Case report of a cutaneous ADR with EV (case report abridged/Krause T et al. 2021):

68-year-old patient with progressive skin lesions under therapy with EV. He had been treated with EV according to the recommended dosing regimen following inductive chemotherapy with gemcitabine/cisplatin and cystectomy for a progressive urothelial carcinoma of the urinary bladder with hepatic, pulmonary, lienal and lymphogenous metastasis first diagnosed in 2017.

Several days after the second EV administration, the patient developed generalized pruritus, papular exanthema of the upper extremity and palmoplantar erythrodysesthesia. From this, non-pruritic, bulging vesicles developed, emphasized on the trunk and upper extremity. Exfoliation of the soles of the feet. Good healing under topical glucocorticoids. The diagnosis was SDRIFE (symmetrical drug related intertriginous and flexural exanthema). Approximately 12 weeks after the first administration of EV (6 administrations in total, the last one 4 weeks before), a vesicular exanthema developed on the forearms on both sides, accentuated on the flexor side. Later, disseminated skin-colored, bulging vesicles and blisters on the arms and trunk. The mucous membranes were not affected and there was no itching. Serologic tests for BP-180/230 and desmoglein 1 and 3 antibodies were negative.

Histology: irregular acanthosis of the epidermis with intraepidermal sharply demarcated blisters. The upper dermis showed a predominantly perivascular lymphocytic infiltrate with scattered eosinophils and melanophages. Direct immunofluorescence showed no evidence of C3, fibrinogen or immunoglobulins. After one week of topical glucocorticoids, vesicles and blisters had completely subsided.

No drug interaction studies have been conducted with enfortumab vedotin. The concomitant use of enfortumab vedotin and medicinal products that are metabolized via CYP3A4 (substrates) does not pose a clinically relevant risk of inducing pharmacokinetic interactions.

Caution is advised with concomitant treatment with CYP3A4 inhibitors. Patients receiving strong CYP3A4 inhibitors at the same time (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) should be monitored more closely for signs of toxicity.

The standard of care for advanced urothelial carcinoma includes platinum-based chemotherapy and inhibitors of programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1). In the platinum-refractory situation, the immune checkpoint inhibitor (ICI) pembrolizumab, which targets PD-1, is considered the standard of care.

1. Eckstein M (2025). NECTIN4 amplification as a predictive biomarker for response to enfortumab vedotin. Pathology (Heidelberg) November 14. German. doi: 10.1007/s00292-025-01496-w.
2. Klümper N et al. (2024) NECTIN4 amplification is common in solid tumors and predicts response to enfortumab vedotin in metastatic urothelial carcinoma. J Clin Oncol 42:2446-2455.

3. Krause T et al. (2021) Marked bullous skin reaction in metastatic urothelial carcinoma treated with enfortumab vedotin: A case report. Journal of the German Dermatological Society 19:1781-1783

4. Wong RL et al. (2022) Enfortumab vedotin in the treatment of urothelial carcinoma and beyond. Future Oncol 18:3067-3084.