FDA Approves Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Bladder Cancer

FDA Approved | Image credit: Olivier Le Moal - stock.adobe.com

The combination of enfortumab vedotin-ejfv (Padcev; Astellas Pharma) and pembrolizumab (Keytruda; Merck) was granted FDA approval for the treatment of patients with locally advanced or metastatic urothelial cancer.¹

Findings from the phase 3 EV-302/KEYNOTE-A39 clinical trial supported the approval. In the trial, the antibody-drug conjugate enfortumab vedotin plus PD-1 inhibitor pembrolizumab nearly doubled both median overall survival (OS) and progression-free survival (PFS) compared with chemotherapy.

These results are unprecedented, with the treatment combination becoming the first in a generation to outperform chemotherapy in the first line. It was lauded as a potential new standard of care when the findings from EV-302 were presented at the European Society for Medical Oncology Congress 2023.²

"Advanced bladder cancer is a common cause of cancer-related death. The overall survival benefit seen in the EV-302 trial demonstrates the potential for [enfortumab vedotin] in combination with pembrolizumab to impact first-line treatment of patients with locally advanced or metastatic urothelial carcinoma. In my opinion, this is a meaningful advancement over platinum-based chemotherapy in the systemic treatment of these patients,” Thomas Powles, MBBS, MRCP, MD, professor of genitourinary oncology and director of the Barts Cancer Centre at St. Bartholomew's Hospital in London, United Kingdom, said in a statement.¹

OS and PFS compared with platinum-containing chemotherapy were dual primary end points in the open-label, randomized, controlled phase 3 trial, which enrolled 886 patients with untreated locally advanced or metastatic urothelial cancer. Patients in the trial were eligible for cisplatin- or carboplatin-containing chemotherapy. Secondary end points included objective response rate, duration of response, and safety.

Patients receiving enfortumab vedotin plus pembrolizumab showed a 53% reduction in the risk of death vs chemotherapy (HR, 0.47; 95% CI, 0.38-0.58; P < .00001), experiencing median OS of 31.5 months (95% CI, 25.4-not reached [NR]) compared with 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm.

Regarding PFS, patients treated with the combination showed a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.38-0.54; P < .00001), with median PFS of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy. Results were consistent across predefined subgroups, which included patients who were cisplatin eligible, cisplatin ineligible, and those with high and low PD-L1 expression.

Safety results were consistent with those previously reported, and the most common all-grade adverse events seen with enfortumab vedotin and 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.

“Today's FDA approval represents a paradigm change in the treatment of advanced bladder cancer and provides hope to the thousands of Americans impacted by this aggressive disease. This achievement is notable, as it is the first regimen approved in advanced urothelial cancer that has demonstrated superiority to platinum chemotherapy, the gold standard of care for decades," Ahsan Arozullah, MD, MPH, senior vice president and head of oncology development at Astellas, said in a statement.

The EV-302 trial is also the confirmatory trial for the April 2023 accelerated approval of enfortumab vedotin in the United States for patients with advanced urothelial cancer who are not eligible for cisplatin-containing chemotherapy. The new approval expands the combination's indication to include those who are eligible to receive cisplatin chemotherapy.

References

1. Padcev (enfortumab vedotin-ejfv) with Keytruda (pembrolizumab) approved by FDA as the first and only ADC plus PD-1 to treat advanced bladder cancer. News release. Astellas US. December 15, 2023. Accessed December 18, 2023. https://newsroom.astellas.us/2023-12-15-PADCEV-R-enfortumab-vedotin-ejfv-with-KEYTRUDA-R-pembrolizumab-Approved-by-FDA-as-the-First-and-Only-ADC-Plus-PD-1-to-Treat-Advanced-Bladder-Cancer

2. Joszt L. First in decades: enfortumab vedotin + pembrolizumab beats chemo in first-line metastatic urothelial cancer. AJMC. October 22, 2023. Accessed December 18, 2023. https://www.ajmc.com/view/first-in-decades-enfortumab-vedotin-pembrolizumab-beats-chemo-in-first-line-metastatic-urothelial-cancer