Enfortumab vedotin plus pembrolizumab confers survival benefit in MIBC

Adding perioperative enfortumab vedotin and pembrolizumab (EV + pembro) to surgery with radical cystectomy plus standard pelvic lymph node dissection (RC + PLND) significantly improves event-free survival (EFS) and overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based therapy, based on the first interim analysis of the phase III KEYNOTE-905 study presented at ESMO 2025.

At a median follow-up of 25.6 months, median EFS was not reached in the EV + pembro arm compared with 15.7 months in the surgery alone arm (hazard ratio [HR], 0.40, 95 percent confidence interval [CI], 0.28–0.57; one-sided p<0.0001). [ESMO 2025, abstract LBA2]

The EV + pembro arm also had higher EFS rates at 12 (77.8 percent vs 55.1 percent) and 24 months (74.7 percent vs 39.4 percent) than the surgery alone arm.

Median OS was also not reached in the EV + pembro arm, whereas it was 41.7 months in the surgery-alone group (HR, 0.50, 95 percent CI, 0.33–0.74; one-sided p=0.0002), with higher OS rates at 12 and 24 months (86.3 percent vs 75.7 percent and 79.7 percent vs 63.1 percent, respectively).

The EFS and OS benefits observed with the EV + pembro arm vs the surgery alone arm were consistent across all subgroups, including age, ECOG performance status, PD-L1, and tumour stage, said lead author Dr Christof Vulsteke from Integrated Cancer Center Ghent in Belgium.

Notably, patients in the experimental arm demonstrated a significantly higher pathological complete response (pCR) rate of 57.1 percent compared with 8.6 percent in the control arm, with an estimated difference of 48.3 percent between the two arms (one-sided p<0.000001). “This is the first phase III trial to report such a high pCR rate,” Vulsteke highlighted.

Safety findings indicated that pruritus (47.3 percent) and alopecia (34.7 percent) were the most common treatment-emergent adverse events in the EV + pembro arm, consistent with prior experience of EV and pembro, noted Vulsteke.

According to Vulsteke, “the overall safety profile of perioperative EV + pembro was manageable and consistent with prior reports of this regimen in the locally advanced/metastatic urothelial carcinoma setting. No new safety signals were observed.”

New standard of care?

This phase III trial analysed 344 patients with MIBC (stage T2–T4N0M0 or T1–T4aN1M0) who were randomized in a 1:1 ratio to EV 1.25 mg/kg on days 1 and 8 Q3W + pembro 200 mg Q3W for three cycles, followed by surgery (RC + PLND) and EV for six cycles + pembro for 14 cycles (EV + pembro arm; n=170), or surgery alone (control arm; n=174).

“Overall, neoadjuvant EV + pembro, followed by surgery and adjuvant EV + pembro significantly and meaningfully improved all endpoints of EFS, OS, and pCR in participants with MIBC, who were ineligible for or declined cisplatin-based chemotherapy, and this benefit was generally consistent across key subgroups,” said Vulsteke.

“KEYNOTE-905 is the first phase III trial to show improved efficacy outcomes with perioperative therapy … Perioperative EV + pembro added to RC + PLND may represent a new standard of care in this population with high unmet medical need,” he added.