Enfortumab vedotin — Drug Monograph

Enfortumab Vedotin (Padcev) — Nectin-4 ADC for Urothelial Carcinoma

Enfortumab vedotin (Padcev) is a Nectin-4-directed antibody-drug conjugate (ADC) for metastatic urothelial carcinoma. Nectin-4 is highly expressed on urothelial cancer cells; after binding and internalization, the cleavable linker releases the microtubule inhibitor MMAE, driving G2/M arrest and apoptosis. Combined with pembrolizumab it is the preferred first-line regimen for metastatic urothelial carcinoma (EV-302) and, as of 2026, perioperative therapy for muscle-invasive bladder cancer (EV-304). This monograph covers enfortumab vedotin dosing (1.25 mg/kg on Days 1, 8, 15), the Nectin-4 ADC mechanism, urothelial carcinoma indications, and management of peripheral neuropathy and severe cutaneous ADC adverse events.

Indications (FDA / NCCN)

• First-line metastatic urothelial carcinoma with pembrolizumab (EV-302), any PD-L1 status
• Perioperative (neoadjuvant + adjuvant) muscle-invasive bladder cancer with pembrolizumab (EV-304)
• Previously treated locally advanced / metastatic urothelial carcinoma

Dosing

• Standard dose: 1.25 mg/kg (max 125 mg) IV over 30 min
• Days 1, 8, and 15 of each 28-day cycle
• No routine premedication required
• Dose reduce for peripheral neuropathy and skin reactions

Monitoring

• Peripheral neuropathy assessment at each visit (cumulative, dose-limiting)
• Severe cutaneous adverse reactions (SJS/TEN) — hold and evaluate
• Blood glucose before each dose (hyperglycemia risk)
• Skin, ocular, and infusion-site reactions

Brand names: Padcev

Drug class: Antibody-Drug Conjugate

Mechanism of Action

Anti-Nectin-4 antibody-drug conjugate. Nectin-4 (PVRL4) is a cell adhesion molecule highly expressed on urothelial carcinoma cells (and many other epithelial tumors). A fully human anti-Nectin-4 IgG1 antibody is conjugated via a cleavable maleimidocaproyl-valine-citrulline-PABA linker to MMAE (monomethyl auristatin E), a microtubule-disrupting agent. After binding Nectin-4 and internalization, linker cleavage releases MMAE, which inhibits microtubule polymerization and induces cell cycle arrest (G2/M) and apoptosis.

FDA Indications

• Locally advanced or metastatic urothelial carcinoma — previously treated with platinum-containing chemotherapy and PD-1 or PD-L1 inhibitor (monotherapy)
• Locally advanced or metastatic urothelial carcinoma — first-line (with pembrolizumab — EV-302/KEYNOTE-869 trial; OS benefit in all subgroups)
• Muscle-invasive bladder cancer (MIBC) — perioperative (neoadjuvant + adjuvant) with pembrolizumab, all patients regardless of cisplatin eligibility (EV-304; July 10, 2026)

Common Side Effects

• Peripheral neuropathy (50%; dose-limiting)
• Fatigue
• Alopecia
• Decreased appetite
• Rash (including maculopapular rash)
• Nausea
• Dysgeusia
• Hyperglycemia
• Pruritus
• Dry eye/ocular symptoms

Clinical Pearl

The EV-302/KEYNOTE-A39 trial (enfortumab vedotin + pembrolizumab vs. platinum-based chemotherapy) in first-line metastatic urothelial carcinoma showed unprecedented OS benefit (median OS 31.5 vs. 16.1 months; HR 0.47) — essentially doubling survival compared to the previous standard. EV + pembro is now the preferred first-line regimen for metastatic UC regardless of PD-L1 status or cisplatin eligibility. As of July 10, 2026, enfortumab vedotin is also approved as perioperative therapy…

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