BERLIN — Perioperative treatment with the antibody-drug conjugate enfortumab vedotin (EV) and the immune checkpoint inhibitor pembrolizumab in muscle-invasive bladder cancer (MIBC) patients who are ineligible or decline cisplatin-related chemotherapy led to dramatic improvements in survival outcomes over surgery alone, in KEYNOTE-905.

Christof Vulsteke, MD, PhD, head of the medical oncology clinical trial service at Integrated Cancer Center Ghent, Belgium, presented the news results of the trial to enthusiastic applause at the European Society for Medical Oncology (ESMO) Annual Meeting 2025 on October 18. The study found a 60% improvement in event-free survival and a 50% increase in overall survival with the addition of the perioperative treatment regimen to radical cystectomy with standard pelvic lymph node dissection (RC+PLND) vs the surgery alone.

“Keynote-905 is the first phase 3 trial to show an improved efficacy outcome with perioperative therapy relative to surgery for patients with MIBC who are ineligible for cisplatin-based chemotherapy,” the author said. Consequently, perioperative EV and pembrolizumab, when added to surgery, “may represent a new standard of care in this population with a high unmet medical need.”

While the standard of care (SOC) for MIBC is neoadjuvant cisplatin-based chemotherapy with the option of perioperative durvalumab or adjuvant nivolumab in high-risk disease and RC+PLND, almost 50% of MIBC patients are ineligible for cisplatin and so have no neoadjuvant options, Vulsteke said. Such patients tend to be older, frailer, and have more comorbidities.

There is, thus far, limited data in this population, but what there is suggests they have poor outcomes with RC+PLND alone, “highlighting a significant unmet medical need,” said Vulsteke. 

Vulsteke explained that, in this context, there is a “strong rationale for investigation in the perioperative setting, in this population” of the combination of EV — which is directed to nectin-4 (a type I transmembrane protein involved in cell-cell adhesion) — and pembrolizumab. 

This is why he and his colleague conducted an open-label phase 3 study that enrolled adults with MIBC who had clinical stage T2-T4aN0M0 or T1-T4aN1M0, had at least 50% urothelial histology, and were either ineligible for, or declined, cisplatin chemotherapy.

Perioperative EV Plus Pembrolizumab vs SOC Surgery Alone

At launch in 2019, the study initially had two arms, with patients assigned to either pembrolizumab for three cycles — followed by RC+PLND and then pembrolizumab for 14 cycles — or a control arm of RC+PLND followed by observation. 

A third arm was added in 2020 allowing patients to be assigned to three cycles of EV plus pembrolizumab, followed by RC+PLND, then six cycles of EV plus 14 cycles of pembrolizumab. Allocation to the arm with pembrolizumab as the only perioperative treatment stopped in 2022, and the study continued with the two remaining arms. Adjuvant nivolumab was allowed in the control arm when clinically indicated and regionally available. 

Between December 15, 2020, and June 6, 2024, 344 patients were randomized, who had a median age of 74.0 years in the EV plus pembrolizumab arm and 72.5 years in the control arm, “which is older than other MIBC trials,” Vulsteke highlighted. 

He also pointed out that 12.4% in the experimental and 14.9% in the control arms had an Eastern Cooperative Oncology Group Performance Status performance status of 2, representing patients who are “typically excluded from other MIBC trials.” The majority (79.9%-83.5%) of patients were ineligible for cisplatin, “most commonly because of renal impairment.” 

Vulsteke also underlined that over three quarters of patients had T3/T4aN0 disease on centrally assessed baseline TNM staging , using a combination of central pathology and imaging, “which rigorously looked at period vesicle extension and involvement into adhesive organs.” 

“To our knowledge, this is the first study that uses a combination of central pathology and imaging for baseline TNM staging,” he said, “because when we are looking at investigator assessed TNM staging, it was just the opposite — clinical stage T2 was predominant — underscoring the need of a standardized approach in TNM staging at baseline, especially in the context of a clinical trial.” 

Turning to the results, he showed that, after a median follow-up of 25.6 months at the data cutoff, the study met its primary endpoint. 

EV plus pembrolizumab was associated with a significant improvement in event-free survival, at a median not reached vs 15.7 months with RC+PLND, at a hazard ratio (HR) of 0.40 (P < .0001). This benefit was seen constantly across key subgroups, Vulsteke said. 

He also reported that the study met its key secondary endpoint of overall survival. The median was once more not reached with perioperative EV plus pembrolizumab vs 41.7 months with RC+PLND alone, at a HR of 50% (P = .0002). This was reflected in the key subgroup analysis. 

Pathologic complete response (pCR) was also far higher with EV plus pembrolizumab than in the control arm, at 57.1% vs 8.6%, or an estimated difference of 48.3% (P < .000001). Vulsteke said this is the first phase 3 trial to show such a high pCR rate, although the low rate in the control arm underlines that those receiving SOC remain at high medical need.

The author underlined that the combination neoadjuvant therapy also did not affect patients’ ability to undergo surgery.

Outside experts also touted the trial’s successes. 

“We are now entering a new era in the treatment of muscle invasive bladder cancer,” commented study discussant Jonathan E. Rosenberg, MD, chief of the genitourinary oncology service at Memorial Sloan Kettering Cancer Center, New York at the meeting. The combination of EV and pembrolizumab “shows dramatic and major clinical benefits” in this patient population, and “can generally be delivered safely and does not result in higher surgical mortality, which I think is a very important point.”

On X (formerly Twitter), Javier Puente, MD, PhD, a medical oncologist and associate professor at Hospital Clinico San Carlos Madrid, Spain, described the results as “practice changing” in bladder cancer and “historic” in cisplatin-ineligible MIBC.

Adverse Events Higher With Perioperative EV Plus Pembrolizumab Than SOC

As expected, EV plus pembrolizumab was associated with an increase in treatment-related adverse events, with grade ≥ 3 events seen in 71.3% of patients vs 45.9% in the control arm. However, there were few events that led to survival delay, at just 4.0%, and rates of adverse events in the surgical phase only were comparable, Vulsteke said.

The most common adverse events with EV plus pembrolizumab were pruritus (47.3%), alopecia (34.7%), and diarrhea (34.1%), which were typically grade 1 and 2. 

Vulsteke added that the most common adverse events of special interest — such as hypo/hyperthyroidism, severe skin reactions, and pneumonitis — were related to pembrolizumab, regardless of whether patients received pembrolizumab plus EV or pembrolizumab alone, perioperatively. 

Rosenberg said the toxicity profile with EV plus pembrolizumab was consistent with prior data, and that the overall survival in the control arm is as expected in this patient population but that there is a lack of survival data for patients undergoing cystectomy. He also noted that the high pCR response with the combination neoadjuvant therapy raises the possibility of bladder preservation with systemic therapy alone.

Study Limitations

The study is limited by only 16.7% of patients in the control arm receiving adjuvant nivolumab, despite it being an option, which likely reflects a lack of local availability, reimbursement, or eligibility, Rosenberg said. 

He also highlighted that patients who refuse cisplatin may not be the same as those who are ineligible for the drug, and there was a signal that combination EV plus pembrolizumab was less effective in this group. However, the small numbers limit any firm conclusions. 

Rosenberg also questioned whether the neoadjuvant phase of the EV plus pembrolizumab regimen was strictly necessary, particularly in patients negative for circulating tumor (ct)DNA and those with a pCR. 

The answer may lie, Rosenberg said, in large, sophisticated randomized trials designed to examine the contribution of each phase of treatment, with perhaps ctDNA as a means of assigning patients to a range of post-surgical management options. 

The study was funded by Merck Sharp & Dohme LLC.

Vulsteke declares relationships with Merck Sharp & Dohme LLC, Janssens-Cilag, GSK, Astellas Pharma, BMS, Leo Pharma, Bayer, AstraZeneca, Pfizer, Merck, and Atheneum Partners.

Rosenberg declares relationships with Acrivon, Astellas, AstraZeneca, BMS, Eli Lilly, Pfizer, Aktis, Araris Biotech, Astellas, Bayer, Boehringer Ingelheim, EMD Serono, Generate Biomedicines, Gilead, Johnson and Johnson, Merck, Natera, Roche Genentech, Samsung Bioepis, Tyra Biosciences, RTP, Medscape, MJH Life Sciences, Clinical Care Options, Mashup Media, Clinical Education Alliance, PSL, Touch Oncology, UpToDate, Medistrava, Ideology Health, and SignifyMD.