Enfortumab Vedotin Plus Pembrolizumab Receives FDA Approval for Advanced Urothelial Carcinoma

For patients with locally advanced or metastatic urothelial carcinoma (bladder and urinary tract cancer) who are ineligible for cisplatin-containing chemotherapy, the combination of enfortumab vedotin-ejfv (Padcev, Astellas Pharma) and pembrolizumab (Keytruda, Merck) received accelerated FDA (US Food and Drug Administration) approval on April 3, 2023.

The significance of this accelerated FDA approval for patients with locally advanced or metastatic (stage 4) urothelial carcinoma is that it offers a more effective and manageable treatment option. This approval represents a major advance, particularly for cisplatin-ineligible patients, in first-line systemic treatment.

FDA Approval Based on EV-103 / KEYNOTE-869

Efficacy was evaluated in the multicohort EV-103/KEYNOTE-869 study (dose-escalation cohort, Cohort A, and Cohort K). The dose-escalation cohort and Cohort A treated patients with enfortumab vedotin-ejfv and pembrolizumab in single arms; patients in Cohort K were randomized to the combination or enfortumab vedotin-ejfv alone. Patients had received no previous systemic treatment for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy. A total of 121 patients received enfortumab vedotin-ejfv plus pembrolizumab.

Results

The primary efficacy outcome measures were objective response rate and duration of response .

• In 121 patients, a confirmed objective response rate of 68% (95% CI: 59, 76), including 12% complete responses , was observed.
• Median duration of response was 22 months (range: 1+ to 46+) for the dose-escalation cohort plus Cohort A and was not determined in Cohort K (range: 1 to 24+).

The most common adverse reactions (>20%), including laboratory abnormalities, were increased glucose, increased aspartate aminotransferase, rash, decreased hemoglobin, increased creatinine, peripheral neuropathy, decreased lymphocytes, fatigue, increased alanine aminotransferase, decreased sodium, increased lipase, decreased albumin, alopecia, decreased phosphate, decreased weight, diarrhea, pruritus, decreased appetite, nausea, dysgeusia, decreased potassium, decreased neutrophils, urinary tract infection, constipation, increased potassium, increased calcium, peripheral edema, dry eye, dizziness, arthralgia, and dry skin.  

For enfortumab vedotin-ejfv given with pembrolizumab, the recommended dose is 1.25 mg/kg (up to 125 mg for patients weighing over 100 kg), administered as a 30-minute intravenous infusion on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. Following enfortumab vedotin on the same day, the recommended pembrolizumab dose is 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months.

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Enfortumab vedotin first received FDA approval in 2019 . In 2021, this approval was expanded as follows: "As a single agent for the treatment of adults with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and have received one or more previous treatments." However, the drug has not yet been licensed in Turkey.

Enfortumab vedotin's mechanism of action is as follows: 

Enfortumab vedotin is an antibody–drug conjugate directed against Nectin-4, a cell-surface protein highly expressed in bladder cancer cells. It is the first FDA-approved Nectin-4-targeted drug.

Enfortumab vedotin exerts its anticancer activity as follows:

1. It binds to Nectin-4-expressing cells.
2. It enables the entry and release of an antitumor agent that disrupts microtubules (the cell skeleton).
3. This process halts cell proliferation and triggers apoptosis (programmed cell death).

Preclinical data suggest that enfortumab vedotin is effective in patients with urothelial cancer through this mechanism. The drug has been developed through a collaboration between Seattle Genetics and Astellas since 2007.