Reference: 2026 | Issue 7 | Vol 12 | Page 41
An interim analysis of the Phase 3 EV-304 trial, also known as KEYNOTE-B15, has demonstrated that perioperative enfortumab vedotin (PADCEV), a Nectin-4-directed antibody-drug conjugate, combined with the PD-1 inhibitor pembrolizumab (Keytruda), significantly improves outcomes for patients with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin-based chemotherapy.
Bladder cancer is the ninth most commonly diagnosed cancer worldwide, with more than 600,000 new cases each year. Approximately 500 people are diagnosed annually in Ireland, and around 30 per cent present with MIBC. Although cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy remains the standard of care for eligible patients, up to half will ultimately develop recurrent or metastatic disease, highlighting the need for more effective perioperative treatment strategies.
EV-304 is an ongoing, international, open-label, randomised phase 3 study comparing perioperative enfortumab vedotin plus pembrolizumab with the current standard of care of neoadjuvant gemcitabine plus cisplatin followed by radical cystectomy. A total of 808 patients were randomised 1:1 to receive either four cycles of neoadjuvant enfortumab vedotin plus pembrolizumab followed by surgery and adjuvant therapy, or standard neoadjuvant chemotherapy followed by surgery.
The trial met its primary endpoint of event-free survival (EFS), with patients receiving enfortumab vedotin plus pembrolizumab experiencing a 47 per cent reduction in the risk of recurrence, progression or death compared with chemotherapy (HR 0.5 [95% CI, 0.41-0.70]; p<0.0001). Median EFS was not reached in the investigational arm versus 48.5 months in the chemotherapy arm, while the estimated two-year EFS rates were 79.4 per cent and 66.2 per cent, respectively.
Overall survival (OS), a key secondary endpoint, also improved significantly, with a 35 per cent reduction in the risk of death (HR=0.65 [95% CI, 0.48-0.89]; p=0.0029). The estimated two-year OS rates were 86.9 per cent with enfortumab vedotin plus pembrolizumab compared with 81.3 per cent for standard chemotherapy. The study also demonstrated a significantly higher pathological complete response (pCR) rate, with 55.8 per cent of patients achieving pCR compared with 32.5 per cent in the chemotherapy arm, an estimated increase of 23.4 per cent ([95% CI, 16.7-29.8]; p<0.0001). The safety profile was consistent with the known effects of the individual agents, with no new safety signals identified. The most common (≥30%) adverse events related to treatment with the combination were pruritus, alopecia, diarrhoea, fatigue, and anaemia.
These findings build on the earlier phase 3 EV-303 (KEYNOTE-905) trial, which evaluated the same combination in patients with resectable MIBC who were ineligible for or declined cisplatin-based chemotherapy. Based on those results, the European Commission approved perioperative enfortumab vedotin plus pembrolizumab as neoadjuvant treatment followed by adjuvant therapy after radical cystectomy, establishing the first approved perioperative treatment option for this patient population in the European Union. EV-303 demonstrated significant improvements in both EFS (HR 0.40) and OS (HR 0.50) compared with surgery alone.
Enfortumab vedotin is a first-in-class antibody-drug conjugate targeting Nectin-4, a protein highly expressed on urothelial cancer cells. After binding to Nectin-4, the drug is internalised and releases the microtubule-disrupting agent monomethyl auristatin E, resulting in cell cycle arrest and apoptosis. Combined with pembrolizumab, the regimen has already transformed the treatment of advanced urothelial cancer and is now the standard first-line treatment for locally advanced or metastatic disease in many countries.
The positive interim results from EV-304 suggest that this combination could also redefine the standard of care for patients with resectable, cisplatin-eligible MIBC, representing the first non-platinum perioperative regimen in more than two decades to outperform standard cisplatin-based chemotherapy.
