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FDA Grants Padcev plus Keytruda Accelerated Approval for Locally Advanced or Metastatic Urothelial Carcinoma

May 2023, Vol 13, No 5

On April 3, 2023, the FDA accelerated the approval of a new indication for enfortumab vedotin-ejfv (Padcev; Astellas Pharma), a Nectin-4–directed antibody and microtubule inhibitor conjugate, with pembrolizumab (Keytruda; Merck), a PD-1 inhibitor, for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. The FDA granted this indication priority review and breakthrough therapy designations. This is the first antibody–drug conjugate and PD-1 inhibitor combination approved in the United States for this patient population.

Enfortumab vedotin was previously approved as monotherapy for certain patients with locally advanced or metastatic urothelial cancer. Pembrolizumab was previously approved as monotherapy for several oncology indications, including certain patients with locally advanced or metastatic urothelial carcinoma or with Bacillus Calmette-Guérin–unresponsive non–muscle-invasive bladder cancer.

This new approval was based on the results of the phase 1b/2 EV-103/KEYNOTE-869 clinical trial, a multicohort study, in which a total of 121 patients received the combination. Patients in the single-arm cohorts—dose-escalation and cohort A—received enfortumab vedotin plus pembrolizumab, whereas patients in cohort K were randomized to treatment with the combination or enfortumab vedotin alone. Participants were ineligible for cisplatin-containing chemotherapy and had not received previous systemic therapy for locally advanced or metastatic disease.

The major efficacy measures were objective response rate (ORR) and duration of response (DOR). In 121 patients, the confirmed ORR was 68% (95% confidence interval, 59-76), including complete responses in 12% of patients. In the dose-escalation group and cohort A, the median DOR was 22 months (range, 1+-46+); the median DOR was not reached in cohort K (range, 1-24+).

The most common (>20%) adverse reactions, 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.

“The accelerated approval for the combination of Padcev and pembrolizumab marks an important milestone for the approximately 8000 to 9000 patients in the United States with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy,” said Ahsan Arozullah, MD, MPH, Senior Vice President, Head of Oncology Development, Astellas.

When the combination of pembrolizumab plus enfortumab vedotin is used, the recommended dose of enfortumab vedotin is 1.25 mg/kg (up to a maximum of 125 mg for patients weighing ≥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.

Pembrolizumab should be administered after enfortumab vedotin on the same day at a recommended dose of 200 mg every 3 weeks or 400 mg every 6 weeks until disease progression, unacceptable toxicity, or up to 24 months.

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