Enfortumab Vedotin

Enfortumab vedotin is an antibody-drug conjugate used primarily in the treatment of urothelial cancer, including bladder cancer. It consists of a monoclonal antibody directed against Nectin-4 that is linked to the microtubule-disrupting agent monomethyl auristatin E. Nectin-4 is expressed on many urothelial cancer cells. After enfortumab vedotin binds to Nectin-4, the conjugate is internalized into the cancer cell and the released drug interferes with microtubule function, disrupting cell division and promoting cell death. Enfortumab vedotin is administered by intravenous infusion and is used either as a single agent or in combination with pembrolizumab, depending on the disease setting and applicable regulatory indication. Current indications include locally advanced or metastatic urothelial cancer and selected muscle-invasive bladder cancer settings. Its clinical importance was established through studies including EV-201, EV-301, EV-103, and EV-302, which evaluated enfortumab vedotin alone or with pembrolizumab in different urothelial cancer populations. The combination with pembrolizumab has also been evaluated in perioperative muscle-invasive bladder cancer.

Enfortumab vedotin was developed as a targeted antibody-drug conjugate designed to deliver a cytotoxic microtubule inhibitor to Nectin-4-expressing cancer cells. The U.S. Food and Drug Administration granted its initial approval in 2019 for previously treated locally advanced or metastatic urothelial cancer, followed by additional approvals expanding its use. In December 2023, the FDA granted regular approval to enfortumab vedotin in combination with pembrolizumab for locally advanced or metastatic urothelial cancer. In November 2025, the FDA approved the combination as neoadjuvant treatment followed by adjuvant treatment after cystectomy for adults with muscle-invasive bladder cancer who were ineligible for cisplatin-containing chemotherapy. In July 2026, the FDA expanded this perioperative indication to adults with muscle-invasive bladder cancer who are candidates for cystectomy, including patients eligible for cisplatin-based chemotherapy. The European Union granted marketing authorization for Padcev in April 2022, with subsequent indication expansions. In India, CDSCO records document approval of enfortumab vedotin in January 2024 for previously treated locally advanced or metastatic urothelial cancer. Major clinical programs include EV-201, EV-301, EV-302, and KEYNOTE-905/EV-303.

Enfortumab vedotin is used in adults with selected urothelial cancers. In the United States, it is indicated in combination with pembrolizumab for locally advanced or metastatic urothelial cancer and for specified perioperative treatment of muscle-invasive bladder cancer. As a single agent, it is indicated for adults with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy, or who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy. In the European Union, enfortumab vedotin with pembrolizumab is indicated for first-line unresectable or metastatic urothelial cancer and for selected resectable muscle-invasive bladder cancer, while monotherapy is used in previously treated locally advanced or metastatic urothelial cancer after platinum chemotherapy and PD-1 or PD-L1 inhibitor treatment. Treatment selection depends on disease stage, previous therapy, surgical eligibility, chemotherapy suitability, and the applicable regulatory indication.

Enfortumab vedotin is administered only by intravenous infusion and should not be given as an intravenous push or bolus. For locally advanced or metastatic urothelial cancer when used with pembrolizumab, the recommended dose is 1.25 mg/kg, up to a maximum of 125 mg, infused over approximately 30 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. When used as a single agent, the recommended dose is 1.25 mg/kg, up to a maximum of 125 mg, on Days 1, 8, and 15 of a 28-day cycle. In the current U.S. perioperative muscle-invasive bladder cancer indication, enfortumab vedotin is administered with pembrolizumab on Days 1 and 8 of 21-day cycles during neoadjuvant and adjuvant treatment according to the approved treatment schedule. Dose interruption, reduction, or discontinuation may be required for significant toxicity. Use should be avoided in patients with moderate or severe hepatic impairment according to current U.S. prescribing information.

Common adverse effects of enfortumab vedotin include rash, fatigue, peripheral neuropathy, decreased appetite, diarrhea, nausea, constipation, changes in taste, hair loss, itching, dry eyes, weight loss, and laboratory abnormalities involving blood counts, liver enzymes, glucose, creatinine, electrolytes, and other parameters. When enfortumab vedotin is combined with pembrolizumab, additional adverse effects may occur because of the combination therapy, including immune-mediated effects associated with pembrolizumab. The frequency and severity of adverse effects vary according to the treatment regimen and individual patient factors. Patients should report new or worsening skin changes, numbness or weakness, vision changes, persistent gastrointestinal symptoms, or other troublesome effects so that treatment can be assessed and supportive measures or dose modification can be considered.

Enfortumab vedotin carries a boxed warning for serious and potentially fatal skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Other important warnings include hyperglycemia and diabetic ketoacidosis, pneumonitis or interstitial lung disease, peripheral neuropathy, ocular disorders, infusion-site extravasation, and embryo-fetal toxicity. Blood glucose should be monitored, particularly in patients with diabetes or risk factors for hyperglycemia. Patients should be monitored for new or worsening respiratory symptoms and neurological symptoms, and treatment interruption, dose reduction, or permanent discontinuation may be required depending on severity. Suspected severe skin reactions require immediate treatment interruption and appropriate specialist assessment, while confirmed Stevens-Johnson syndrome or toxic epidermal necrolysis requires permanent discontinuation.

Before treatment, clinicians should review the patient's cancer history, previous systemic therapies, suitability for combination treatment, hepatic function, glucose status, neurological history, skin condition, respiratory history, ocular symptoms, and concomitant medicines. Enfortumab vedotin can cause clinically important hyperglycemia and should be used with careful glucose monitoring in patients with diabetes or other risk factors. Peripheral neuropathy should be assessed before and during treatment, particularly in patients with pre-existing neurological symptoms. Current prescribing information identifies increased exposure to the cytotoxic component MMAE when enfortumab vedotin is administered with medicines that are both P-glycoprotein and strong CYP3A4 inhibitors. Pregnancy should be avoided during treatment because enfortumab vedotin can cause fetal harm, and breastfeeding is not recommended during treatment.

Treatment should be initiated and supervised by clinicians experienced in systemic cancer therapy. Confirm the urothelial cancer setting, previous treatment history, and whether enfortumab vedotin is being used alone or with pembrolizumab. Baseline assessment should include skin examination, glucose status, neurological symptoms, hepatic function, respiratory status, and relevant ocular symptoms. Patients should be counselled to report rapidly developing rash, blistering, skin peeling, fever, breathing difficulty, new numbness or weakness, changes in vision, or symptoms of severe hyperglycemia. Pharmacists should verify weight-based dosing, maximum dose limits, infusion preparation, treatment-cycle schedule, and potential drug interactions. The infusion site should be monitored because extravasation can cause local tissue injury. When combined with pembrolizumab, monitoring should also account for immune-mediated adverse reactions associated with the immunotherapy component.