Enfortumab Vedotin-ejfv Plus Pembrolizumab Approved for Urothelial Cancer

The FDA has approved enfortumab vedotin-ejfv (Padcev®, Astellas Pharma) in combination with pembrolizumab (Keytruda®, Merck) for patients with locally advanced or metastatic urothelial cancer (UC). The FDA previously granted accelerated approval for this therapy combination for patients with locally advanced or metastatic UC who are ineligible for cisplatin-containing chemotherapy.  

Why it matters: “Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic UC; however, toxicity is substantial, responses are rarely durable, and many patients are ineligible,” wrote Christopher Hoimes, DO, Professor of Medicine at Duke University School of Medicine, and colleagues, in their published results of the EV-302/KN-A39 trial (NCT04223856), on which approval was based. “Each enfortumab vedotin and pembrolizumab have shown a survival benefit versus chemotherapy in UC, are not restricted by cisplatin eligibility, and warrant investigation as a first-line combination therapy in patients ineligible for cisplatin.”

What they studied: Efficacy was measured in the phase 3, open-label trial in which 886 patients with locally advanced or metastatic UC with no prior systemic therapy for advanced disease were enrolled. Patients were randomized 1:1 to receive either enfortumab vedotin-ejfv with pembrolizumab or platinum-based chemotherapy, consisting of gemcitabine with either cisplatin or carboplatin. Stratification criteria for randomization included the patients’ cisplatin eligibility, programmed death-ligand 1 (PD-L1) expression, and presence of liver metastases.

The primary end points studied were overall survival and progression-free survival as assessed by blinded independent central review.

What they found: Overall survival and progression-free survival both saw statistically significant improvements for patients being treated with enfortumab vedotin-ejfv plus pembrolizumab. The median overall survival for those being treated with enfortumab vedotin-ejfv plus pembrolizumab was 31.5 months compared with those receiving platinum-based chemotherapy at a median of 16.1 months. The median progression-free survival for those receiving enfortumab vedotin-ejfv plus pembrolizumab was 12.5 months compared with those receiving platinum-based chemotherapy at a median of 6.3 months.

Adverse events: The most common adverse events, including laboratory abnormalities, experienced by ≥20% of patients receiving enfortumab vedotin-ejfv with pembrolizumab were increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection, and decreased platelets.

Conclusion: “Enfortumab vedotin plus pembrolizumab showed a manageable safety profile,” concluded Dr. Hoimes and colleagues. “Most patients experienced tumor shrinkage. The median duration of response and median overall survival exceeding two years in a cisplatin-ineligible patient population make this a promising combination currently under investigation in a phase 3 study.”

Instructions: The recommended dosage of enfortumab vedotin-ejfv when given with pembrolizumab is 1.25 mg/kg, up to a maximum of 125 mg for patients ≥100 kg, administered as an intravenous infusion over 30 minutes on Days 1 and 8 of a 21-day cycle, until disease progression or unacceptable toxicity.

The recommended dosage of pembrolizumab when given with enfortumab vedotin-ejfv is 200 mg administered as an intravenous infusion every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or two years of therapy.

For More Information

Hoimes CJ, Flaig TW, Milowsky MI, et al (2023). Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol, 41(1):22-31. DOI:10.1200/JCO.22.01643

Clinicaltrials.gov (2023). Enfortumab vedotin and pembrolizumab vs. chemotherapy alone in untreated locally advanced or metastatic urothelial cancer (EV-302). NLM identifier: NCT04223856.

Padcev® (enfortumab vedotin-ejfv) prescribing information (2023). Astellas Pharma. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761137s007lbl.pdf

Keytruda® (pembrolizumab) prescribing information (2023). Merck and Co, inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s066lbl.pdf

US Food and Drug Administration (2023). FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer

Image credit: CoRus13. Licensed under CC0 1.O

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