Perioperative enfortumab vedotin and pembrolizumab has delivered unprecedented survival and response rates in cisplatin-ineligible muscle-invasive bladder cancer, signalling a potential new standard of care.
Patients with muscle-invasive bladder cancer who are unable to receive cisplatin-based chemotherapy have long faced poorer outcomes and limited treatment options.
Now, results from the phase 3 KEYNOTE-905 trial suggest a combination of enfortumab vedotin and pembrolizumab could dramatically alter that landscape, delivering major gains in survival and tumour eradication before surgery.
Published in The New England Journal of Medicine, the international study enrolled 344 patients with clinically non-metastatic muscle-invasive bladder cancer who were either ineligible for cisplatin-based chemotherapy or had declined it.
Participants were randomised to receive perioperative treatment with the nectin-4-targeted antibody-drug conjugate enfortumab vedotin plus the PD-1 inhibitor pembrolizumab before and after radical cystectomy, or surgery alone.
The trial population reflected the reality of routine practice. Median age was 73 years, more than 80% of participants were aged 65 years or older, and more than four in five were deemed cisplatin-ineligible.
Reduced renal function was the most common reason patients could not receive standard cisplatin-based therapy. More than three-quarters had locally advanced T3 or T4 disease at baseline.
Patients assigned to the experimental arm received three neoadjuvant cycles of enfortumab vedotin and pembrolizumab before surgery, followed by six cycles of adjuvant enfortumab vedotin and up to 14 cycles of adjuvant pembrolizumab. Nearly 88% ultimately proceeded to surgery, comparable to the control group.
At a median follow-up of 25.6 months, investigators reported a striking improvement in the primary endpoint of event-free survival. An event or death occurred in 28.2% of patients receiving enfortumab vedotin and pembrolizumab compared with 54.6% of those treated with surgery alone.
The risk of progression, recurrence, or death was reduced by 60%, with two-year event-free survival rates of 74.7% versus 39.4%. Median event-free survival had not yet been reached in the treatment arm, compared with 15.7 months in the control arm.
The benefit extended to overall survival, a key secondary endpoint. Two-year overall survival reached 79.7% in the perioperative treatment group compared with 63.1% among patients undergoing surgery alone. The combination reduced the risk of death by 50%, with median overall survival not yet reached in the treatment arm.
The researchers highlighted the pathological complete response rate as one of the most notable results.
Central pathological review found no residual viable tumour in 57.1% of patients treated with enfortumab vedotin and pembrolizumab, compared with just 8.6% in the surgery-alone group. Pathological downstaging below pT2N0 occurred in 65.9% versus 12.6% of patients respectively.
“Perioperative enfortumab vedotin plus pembrolizumab led to significant improvements in event-free survival, overall survival, and pathological complete response among patients who were not eligible for or declined cisplatin-based neoadjuvant chemotherapy, with a risk of adverse events previously associated with the combination therapy,” the researchers concluded.
“On the basis of this trial, the [US] Food and Drug Administration approved neoadjuvant followed by adjuvant enfortumab vedotin plus pembrolizumab after cystectomy as a new treatment option for adults with muscle-invasive bladder cancer who are ineligible for cisplatin; regulatory review in other regions is ongoing.”
An accompanying editorial described the findings as a potential paradigm shift for a group of patients who have historically lacked effective curative-intent options.
Editorialists Dr Parminder Singh and Professor Seth Lerner noted that more than 80% of trial participants had stage III disease and many would traditionally have been regarded as poor candidates for bladder-preserving approaches.
Despite these unfavourable characteristics, pathological complete response rates substantially exceeded those reported in many previous neoadjuvant chemotherapy studies.
“The findings from the KEYNOTE-905 trial could fundamentally reshape patient selection for bladder preservation,” they wrote.
Related
“These patients with unfavourable disease characteristics could potentially become viable candidates for bladder-sparing approaches after treatment with neoadjuvant enfortumab vedotin plus pembrolizumab.
“Furthermore, for patients who are ineligible for concurrent chemoradiation or radical cystectomy, systemic therapy with enfortumab vedotin plus pembrolizumab could offer durable local disease control and meaningful symptom relief, thereby improving quality of life.”
“Strong efficacy” in a predominantly cisplatin-ineligible population highlighted the potential for the regimen to extend curative treatment to patients who previously had few options beyond surgery alone, they wrote.
The authors said the trial also challenged the long-standing assumption that maximal transurethral resection of the bladder tumour was an essential prerequisite for trimodal therapy.
“If a highly active systemic regimen can result in substantial downstaging before radiation, the use of extensive transurethral resection, and its associated morbidity, may be reduced,” they wrote.
“Indeed, retrospective studies have shown a high incidence of grade 2 and 3 complications after transurethral resection of the bladder tumour, especially among older patients (>60 years of age).”
Despite the impressive results, the authors cautioned that several important questions remained.
The long-term safety of radiotherapy following treatment with enfortumab vedotin and pembrolizumab has yet to be established, including the potential risks of radiation cystitis, increased local toxicity, and bladder dysfunction.
Further research was also needed to determine which patients benefit most from the regimen, particularly whether outcomes were strongest in those with more advanced local disease.
“Future trials, such as the proposed phase 3 SWOG trial assessing enfortumab vedotin plus pembrolizumab followed by trimodal therapy as compared with trimodal therapy alone, will be pivotal in determining whether enfortumab vedotin plus pembrolizumab can safely and effectively serve as a neoadjuvant platform for bladder preservation,” the editorial authors concluded.
Article: The New England Journal of Medicine, February 2026
Editorial: The New England Journal of Medicine, February 2026
