Early results from the phase 3 EV-304 clinical trial suggest that a combination of enfortumab vedotin (Padcev; Astellas Pharma Inc) and pembrolizumab (Keytruda; Merck & Co) could offer a new, platinum-free treatment option for patients with muscle-invasive bladder cancer (MIBC).
The ongoing, open-label trial is testing this combination as a pre- and post-surgery (neoadjuvant and adjuvant) treatment, comparing it to standard chemotherapy for patients eligible for cisplatin-based regimens.
“Building on the recent U.S. approval for patients ineligible for cisplatin, these findings highlight the potential of enfortumab vedotin plus pembrolizumab to improve survival for a wide range of MIBC patients,” said Moitreyee Chatterjee-Kishore, PhD, MBA, Head of Oncology Development at Astellas. “Along with EV-303 results, these studies strengthen the evidence for this combination as a new treatment option.”
Understanding Muscle-Invasive Bladder Cancer
MIBC affects the detrusor muscle, a thick layer of the bladder wall, and is more likely to spread to other organs. It represents nearly 30% of all bladder cancer cases and is the third most common cancer among men in the U.S., especially those aged 75–84.
Current treatments include bladder removal (cystectomy) with or without chemotherapy, chemotherapy combined with radiation, or transurethral tumor removal. Despite these options, about half of MIBC patients develop metastatic disease within three years of diagnosis, explained Dr. Christopher Hoimes, director of the bladder cancer program at Duke Cancer Institute and EV-304 principal investigator.
How Enfortumab Vedotin Works
Enfortumab vedotin is a first-of-its-kind antibody-drug conjugate that targets Nectin-4, a protein highly expressed on bladder cancer cells. Once attached to these cells, it delivers a toxic payload called monomethyl auristatin E (MMAE), which blocks cell division and triggers cancer cell death.
“For the first time, MIBC patients may see survival benefits from combination therapy without platinum chemotherapy, signaling a potential new standard of care,” said Jeff Legos, PhD, MBA, Chief Oncology Officer at Pfizer.
Key Findings from EV-304 and EV-303 Trials
In EV-304, researchers compared enfortumab vedotin plus pembrolizumab with standard chemotherapy (gemcitabine and cisplatin) in cisplatin-eligible patients. The study met its primary goals, showing significant improvements in both event-free survival and overall survival.
The EV-303 trial also demonstrated that this combination improved survival compared to surgery alone. Together, these results suggest that enfortumab vedotin plus pembrolizumab could become a new platinum-free standard for early-stage bladder cancer.
“The EV-304 findings mark an important milestone in urothelial cancer treatment,” said Chatterjee-Kishore. “These studies show that perioperative enfortumab vedotin plus pembrolizumab can improve outcomes for both cisplatin-eligible and ineligible patients, offering a potential shift from conventional chemotherapy and transforming the standard of care.”
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