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Thomas Flaig, MD


FDA Brief: Antibody-Drug Conjugate and PD-1 Inhibitor Combination Granted Accelerated Approval in Advanced Urothelial Cancer

By: JNCCN 360 Staff
Posted: Tuesday, April 4, 2023

On April 3, Astellas Pharma and Seagen announced that the U.S. Food and Drug Administration (FDA) granted accelerated approval to the combination of enfortumab vedotin-ejfv (Padcev) with pembrolizumab (Keytruda) in the treatment of adults with locally advanced or metastatic urothelial cancer who are not eligible to receive cisplatin-containing chemotherapy. Continued approval of this indication is contingent upon verification and description of clinical benefit in the confirmatory EV-302 trial.

Efficacy was evaluated in EV-103/KEYNOTE-869, a multicohort (dose-escalation cohort, Cohort A, Cohort K) study. Results from EV-103 Cohort K on this combination therapy were presented at the European Society for Medical Oncology (ESMO) Congress 2022. The dose-escalation cohort and Cohort A were single-arm cohorts treating patients with enfortumab vedotin plus pembrolizumab, whereas patients on Cohort K were randomly assigned to receive either the combination or enfortumab vedotin alone. Patients had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy. A total of 121 patients received enfortumab vedotin plus pembrolizumab.

The major efficacy outcome measures were objective response rate and duration of response, determined by blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1. The confirmed objective response rate in 121 patients was 68% (95% confidence interval = 59%–76%), including 12% with complete responses. The median duration of response for the dose-escalation cohort and Cohort A was 22 months, and for Cohort K, it was not reached.

The most common adverse reactions (> 20%) with the combination therapy, 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, potassium increased, calcium increased, peripheral edema, dry eye, dizziness, arthralgia, and dry skin. 

The recommended dose of enfortumab vedotin 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 pembrolizumab dose, administered after enfortumab vedotin on the same day, is 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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