KEYNOTE-905 data on EV/pembro in MIBC published in NEJM

Data from the KEYNOTE-905/EV-303 trial (NCT03924895) have been published in the New England Journal of Medicine, showing that perioperative enfortumab vedotin-ejfv (EV; Padcev) plus pembrolizumab (Keytruda) significantly extends event-free (EFS) and overall survival (OS) vs surgery alone in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy.¹

The results were initially presented at the 2025 European Society for Medical Oncology (ESMO) Congress in Berlin, Germany.

“Given the magnitude of the event-free survival and overall survival benefit, this represents yet another paradigm shift in the treatment of bladder cancer,” said lead author Professor Christof Vulsteke, MD, PhD, head of the Integrated Cancer Center Ghent, in correspondence with Urology Times®. “The pathological complete response rate of 57.1% makes us dream of a future in which the bladder may no longer need to be removed or irradiated.”

In total, the study included 344 patients who were randomly assigned to receive neoadjuvant and adjuvant EV/P (n = 170) or to surgery alone (control) (n = 174). The median follow-up was 25.6 months (range, 11.8 to 53.7). The primary end point was EFS, and key secondary end points were OS and pathological complete response, defined as the absence of viable tumor after surgical resection. Safety was also assessed.

At 2 years, the estimated EFS was 74.7% in the EV/P arm compared with 39.4% in the control arm (HR, 0.40; 95% CI, 0.28 to 0.57; two-sided P < .001). The median duration of EFS was not reached in the EV/P arm and was 15.7 months (95% CI, 10.3 to 20.5) in the control arm.

Further, the estimated OS was 79.7% in the EV/P arm vs 63.1% in the control arm (HR, 0.50; 95% CI, 0.33 to 0.74; two-sided P < .001). The median duration of OS was not reached in the treatment arm and was 41.7 months (95% CI, 31.8 to not reached) in the control arm.

According to the authors, “Event-free survival and overall survival outcomes among most key subgroups were consistent with those in the intention-to-treat population, although the numbers of events in some subgroups were low.”

Data also showed a pathological complete response rate of 57.1% in the EV/P arm compared with 8.6% in the control arm (estimated difference, 48.3 percentage points; 95% CI, 39.5 to 56.5; two-sided P < .001). Pathological downstaging occurred in 65.9% of patients in the EV/P arm vs 12.6% of patients in the control arm (estimated difference, 53.1 percentage points; 95% CI, 44.0 to 61.2).

Regarding safety, adverse events (AEs) were reported in all patients in the EV/P arm and 64.8% in the control arm. In the EV/P arm, the most common AEs of any grade were pruritus (in 47.3%) and alopecia (in 34.7%).

Grade 3 AEs occurred in 71.3% of patients in the treatment cohort and 45.9% of patients in the control cohort. Serious adverse events were reported in 58.1% of patients in the EV/P arm and 40.9% of patients in the control arm. AEs led to death in 7.8% and 5.7% of patients, respectively.

Results from the KEYNOTE-905 trial led to FDA approval of pembrolizumab and pembrolizumab and berahyaluronidase alfa-pmph (Keytruda QLEX), each in combination with enfortumab vedotin, as perioperative regimens for cisplatin-ineligible MIBC in November 2025.²

The perioperative regimen was also explored in the KEYNOTE-B15 trial (NCT04700124) in cisplatin-eligible patients. Topline results from the trial were reported in December 2025,³ showing that the combination yielded significant improvements in EFS, OS, and pathologic complete response rates vs neoadjuvant chemotherapy and surgery. Full results are set to be presented at the upcoming 2026 ASCO Genitourinary Cancers Symposium in San Francisco, California.

Overall, Vulsteke concluded, “Robust response adapted trials incorporating circulating and urinary tumor DNA will define the next frontier in precision bladder cancer care.”

REFERENCES

1. Vulsteke C, Adra N, Danchaivijitr P, et al. Perioperative enfortumab vedotin and pembrolizumab in bladder cancer. N Engl J Med. 2026. doi:10.1056/NEJMoa2511674

2. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. US Food & Drug Adminstration. November 21, 2025. Accessed February 19, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer?utm_medium=email&utm_source=govdelivery

3. First and only immunotherapy plus ADC regimen, used perioperatively, to extend survival for cisplatin-eligible patients with MIBC. News release. Merck. December 17, 2025. Accessed February 19, 2026. https://www.merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-significantly-improved-event-free-survival-overall-survival-and-pathologic-complete-response-rates-for-cisplatin-eligible-pa/