Results showing that the combination of enfortumab vedotin and pembrolizumab produced “dramatic improvements” in survival were greeted with cheers.
Patients with muscle-invasive bladder cancer (MIBC) who either were ineligible for cisplatin-based chemotherapy or refused to receive it showed “dramatic improvements” in event-free survival (EFS), overall survival (OS), and pathologic complete response (pCR) rates with the perioperative combination of the antibody-drug conjugate enfortumab vedotin (Padcev) and the immune checkpoint inhibitor pembrolizumab (Keytruda) compared with those who received radical cystectomy and pelvic lymph node dissection alone.
Findings from the phase 3 KEYNOTE-905 trial were met with loud applause and appreciative whistles from the audience when they were presented during an oral abstract session at the 2025 European Society for Medical Oncology (ESMO) Annual Congress (LBA2).
“This is the first trial to show an overall survival benefit in this population,” said Christof Vulsteke, MD, PhD, from the Integrated Cancer Centre Ghent in Belgium, who presented the data during a presidential symposium.
The combination of enfortumab vedotin and pembrolizumab (EV+P) in the neoadjuvant and adjuvant settings was associated with a 60% improvement in the primary endpoint of independently confirmed EFS in the intention-to-treat population, a 50% reduction in the risk for death, and a pCR of 57.1% compared with 8.6% for patients in the control group.
Calling Dr. Vustelke’s presentation “a hard act to follow,” invited discussant Jonathan E. Rosenberg, MD, from the Memorial Sloan Kettering Cancer Center in New York City, commented that “we are now entering a new era in the treatment of muscle-invasive bladder cancer.”
“Enfortumab vedotin plus pembrolizumab shows dramatic and major clinical benefits in patients who are cisplatin ineligible or refusing cisplatin-based chemotherapy for muscle-invasive bladder cancer. The treatment can generally be delivered safely and does not result in higher surgical mortality, which I think is a very important point,” Dr. Rosenberg said.
KEYNOTE-905 was initiated in 2019 and compared perioperative pembrolizumab with radical cystectomy and pelvic lymph node dissection versus surgery alone. A third group receiving perioperative EV+P was added in 2020, based on promising results in the metastatic setting. In 2022, the inclusion criteria were expanded to include cisplatin-eligible patients who declined cisplatin-based chemotherapy. That same year, the pembrolizumab plus surgery group was halted.
At ESMO 2025, Dr. Vulsteke presented results for all patients concurrently randomly assigned to receive EV+P or controls. The patients were adults with MIBC clinical stage T2–T4aN0M0 or T1–T4N1M0 and 50% or greater urothelial histology. The patients were either ineligible for cisplatin, according to the Galsky criteria, or declined cisplatin treatment.
After stratification by cisplatin eligibility, clinical stage, and treatment region, the patients were randomly assigned either to surgery and observation or to neoadjuvant enfortumab vedotin at 1.25 mg/kg intravenously (IV) on days one and eight every three weeks for three cycles plus pembrolizumab at 200 mg IV every three weeks for three cycles, along with surgery and adjuvant enfortumab vedotin at the same dose and cycle length as in the neoadjuvant period for six cycles and pembrolizumab at the same dose and cycle length for 14 cycles (52 weeks total).
The median age of the intention-to-treat population was 74.0 years in the EV+P group (170 patients) and 72.5 years in the control group (174 patients). In each group, approximately 80% of patients were ineligible for cisplatin because of comorbidities, frailty, advanced age, or other reasons. The remaining patients declined to receive cisplatin-based chemotherapy.
The median follow-up at the time of data cutoff in June 2025 was 25.6 months. In all, 87.6% of patients in the EV+P group and 89.7% in the control group were able to undergo surgery.
The median EFS was not reached (95% confidence interval [CI], 37.3 months to not reached) in the EV+P group compared with 15.7 months (95% CI, 10.3–20.5 months) in the control group. This difference translated into a hazard ratio (HR) of 0.40 (95% CI, 0.28–0.57; P<.0001).
The secondary endpoints of OS and pCR rates also clearly favored the combination. The median OS was not reached in the EV+P group (95% CI, not reached to not reached) compared with 41.7 months in the control group (95% CI, 31.8 months to NR). This translates to an HR of 0.50 (95% CI, 0.33–0.74; P=.0002).
Similarly, the respective pCR rates were 57.1% (95% CI, 49.3%–64.6%) compared with 8.6% (95% CI, 4.9%–13.8%), for an estimated difference of 48.3% (95% CI, 39.5%–56.5%; P<.000001). “This is the first phase 3 trial that ever has reported such high path CR rates,” Dr. Vulsteke said. He added that an exploratory analysis showed benefit with EV+P regardless of pCR status.
All patients who received EV+P had treatment-emergent adverse events (TEAEs), 71.3% of which were grade 3 or greater. In contrast, 64.8% of patients in the control group had any TEAE (45.9% grade 3 or greater). The most frequent grade 3 or greater events of special interest, based on distinct prespecified lists for each drug, were severe skin reactions associated with pembrolizumab and skin reactions associated with enfortumab vedotin.
Thirteen patients in the combination therapy group and nine in the control group had fatal TEAEs. Four of the 13 deaths in the EV+P group and all the deaths in the control group occurred during the surgery phase of treatment.
In his discussion, Dr. Roseberg said that large randomized trials are still needed to determine the relative contributions of treatment phase to outcomes. He also cited several questions that still need to be addressed, regarding options for treating metastatic disease after EV+P.
KEYNOTE-905 is funded by Merck.
Dr. Vulsteke reported research funding and medical writing support from Merck Sharp & Dohme, and advisory board activity for MSD, Janssens-Cilag, GlaxoSmithKline, Astellas Pharma, BMS, Leo Pharma, Bayer, AstraZeneca, Pfizer, Merck, and Atheneum Partners.
Dr. Rosenberg reported various financial relationships.
