A perioperative regimen of the antibody-drug conjugate enfortumab vedotin-ejfv plus the PD-1 inhibitor pembrolizumab significantly improved outcomes vs radical cystectomy alone in patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy. Results from the phase III KEYNOTE-905/EV-303 study were presented by Christof Vulsteke, MD, PhD, Head of Integrated Cancer Center Ghent and Guest Professor at the University of Antwerp, Belgium, at the European Society for Medical Oncology (ESMO) Congress 2025.¹ These findings were met with spontaneous applause from the audience of doctors and scientists.

Christof Vulsteke, MD, PhD

The study demonstrated an improvement in clinical outcomes, with median overall survival not yet reached with enfortumab vedotin plus pembrolizumab compared with 41.7 months in the control arm (hazard ratio [HR] = 0.50; P < .0002). Furthermore, the pathologic complete response rate with the combination reached 57.1%, dramatically higher than the 8.6% observed with surgery alone (estimated difference 48.3%; P < .001).

“KEYNOTE-905 is the first phase III trial to show an improved efficacy outcome with perioperative therapy relative to surgery for patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy,” said Dr. Vulsteke. “Preoperative enfortumab vedotin and pembrolizumab added to surgery may represent a new standard of care in this population.”

As Dr. Vulsteke explained, radical cystectomy plus pelvic lymph node dissection is the established standard for muscle-invasive bladder cancer. However, nearly half of patients with muscle-invasive bladder cancer are ineligible for cisplatin-based chemotherapy because of comorbidities such as renal impairment, hearing loss, or poor performance status. These cisplatin-ineligible patients, who are often older and frailer, have historically lacked effective neoadjuvant treatment options and face poorer outcomes with surgery alone.

“This highlights a critical unmet medical need that no prior phase III perioperative trial has successfully addressed,” said Dr. Vulsteke. He noted that the combination of enfortumab vedotin, an antibody-drug conjugate targeting Nectin-4, and pembrolizumab, a PD-1 immune checkpoint inhibitor, presented a strong rationale for investigation in this setting, having shown activity in metastatic urothelial carcinoma.

Study Methods

The KEYNOTE-905/EV-303 study was a global, open-label trial that enrolled 344 adults with muscle-invasive bladder cancer (clinical stage T2–T4aN0M0 or T1–T4aN1M0) of predominant urothelial histology, who were either cisplatin-ineligible (per modified Galsky criteria) or declined cisplatin. Patients were randomly assigned 1:1 to receive either perioperative enfortumab vedotin plus pembrolizumab (n = 170) or radical cystectomy plus pelvic lymph node dissection alone (control arm; n = 174).

The experimental arm consisted of three cycles of neoadjuvant enfortumab vedotin (1.25 mg/kg on days 1 and 8) plus pembrolizumab (200 mg on day 1) every 3 weeks, followed by radical cystectomy plus pelvic lymph node dissection, and then 6 cycles of adjuvant enfortumab vedotin plus 14 cycles of adjuvant pembrolizumab. Treatment continued until disease progression, unacceptable adverse events, withdrawal of patient consent, or completion of planned treatment.

The primary endpoint was event-free survival by blinded independent central review. Key secondary endpoints included overall survival and pathologic complete response rate.

Median follow-up was 25.6 months. The patient population reflected the target group, with a median age of 73 years, 14% having an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (typically excluded from other muscle-invasive bladder cancer trials), and more than 80% being cisplatin-ineligible (most commonly due to renal impairment). More than 75% of patients had a clinical stage of T3–T4a, as determined by a rigorous combination of central pathology and imaging for baseline TNM staging.

Improvement Across All Efficacy Endpoints

The combination of enfortumab vedotin plus pembrolizumab significantly improved event-free survival (median not reached vs 15.7 months; HR = 0.40; P < .0001). There was an early and sustained separation of the event-free survival curves, with this benefit consistent across key subgroups including age, ECOG performance status, PD-L1 status, and TNM stage. The key secondary endpoint of overall survival was also significantly improved, with a median overall survival of not reached with enfortumab vedotin plus pembrolizumab compared with 41.7 months in the control arm (P < .0002).

“There was early and a sustained separation of the curves resulting in a statistically significant hazard ratio of 0.5,” said Dr. Vulsteke. “This is the first trial to show an overall survival benefit in this population.”

Subsequent therapies in the recurrent or metastatic setting were received by 4.7% in the arm given enfortumab vedotin plus pembrolizumab and 26.4% in the control arm.

The pathologic complete response rate was higher with enfortumab vedotin plus pembrolizumab at 57.1% compared with 8.6% in the control arm (estimated difference, 48.3%; P < .000001). According to Dr. Vulsteke, this represents an unprecedented pathologic complete response rate for patients with muscle-invasive bladder cancer in a phase III setting.

An exploratory analysis indicated that event-free survival benefits with enfortumab vedotin plus pembrolizumab were observed irrespective of achieving a pathologic complete response. The combination regimen did not impede the ability of patients to undergo curative-intent surgery, commented Dr. Vulsteke, with similar proportions of patients in both arms proceeding to surgery (87.6% vs 89.7%).

Safety Profile

The overall safety profile of enfortumab vedotin plus pembrolizumab was reported to be manageable and consistent with prior experience of this regimen in the metastatic setting. Treatment-emergent adverse events occurred in 100% of patients given enfortumab vedotin plus pembrolizumab (71.3% grade 3 or higher) vs 64.8% in the control arm (45.9% grade 3 or higher). Most common grade 3 or higher adverse events in the combination arm were hematologic and gastrointestinal toxicities, mainly during the induction phase.

Adverse events of special interest related to the use of enfortumab vedotin (eg, skin reactions and polyneuropathy) and pembrolizumab (eg, grouped skin reactions) were most commonly grade 1 or 2. Adverse events leading to surgical delay were few, according to the investigators, and adverse events during the surgical phase (including serious adverse events and those leading to death) were found to be similar between both arms.

DISCLOSURE: Dr. Vulsteke reported financial relationships with MSD, Janssen-Cilag, GSK, Astellas Pharma, BMS, Leo Pharma, Bayer, AstraZeneca, Pfizer, and Merck.

REFERENCE

1. Vulsteke C, Kaimakliotis H, Danchaivijitr P, et al: Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: The phase 3 KEYNOTE-905 study. ESMO Congress 2025. Abstract LBA2. Presented October 18, 2025.

EXPERT POINT OF VIEW

Invited discussant of the KEYNOTE-905/EV-303 trial, Jonathan E. Rosenberg, MD, underscored the clinical benefits of enfortumab vedotin plus pembrolizumab in patients who are cisplatin-ineligible or declined cisplatin-based chemotherapy. Dr. Rosenberg is Chief of the Genitourinary Oncology Service and Attending Physician at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College, New York.

Jonathan E. Rosenberg, MD

“The field is now entering a new era in the treatment of muscle-invasive bladder cancer,” said Dr. Rosenberg. He highlighted the fact that the treatment can be delivered safely, noting it “does not result in higher surgical mortality.” According to Dr. Rosenberg, this safety profile is particularly significant given the advanced age (median patient age, 74 years) and comorbidities of the patient population enrolled in KEYNOTE-905/EV-303, a group historically excluded from many trials.

In addition, Dr. Rosenberg described the event-free survival improvement as “remarkable” and the overall survival hazard ratio of 0.5 as suggesting the “toxicity is worthwhile.” He lauded the unprecedented pathologic complete response rate of 57.1% (or 63% per protocol), stating it “set a new high bar” in a randomized phase III setting. This high rate, he added, “raises the possibility of bladder preservation with systemic therapy alone,” a paradigm-shifting concept that warrants further exploration, albeit with considerations for the field cancerization effect in urothelial cancer.

Remaining Questions and Study Limitations

Despite the groundbreaking results, Dr. Rosenberg raised several critical questions for future clinical practice and research. A major concern is understanding the “contribution of phase”—whether the neoadjuvant or adjuvant components (or both) are primarily driving the observed benefits. Dr. Rosenberg questioned whether patients achieving a pathologic complete response or those who are circulating tumor DNA–negative after surgery still require the full adjuvant regimen. Adjuvant immunotherapy was not administered to most control arm patients, he noted, and many patients in the experimental arm (about one-third) did not receive the intended adjuvant treatment, underscoring the real-world challenges of adherence.

Dr. Rosenberg acknowledged some study limitations. They include potential differences between cisplatin-ineligible and cisplatin-declining patients and the likely lack of enfortumab vedotin plus pembrolizumab access for control arm patients at relapse. However, he added, “I don’t think any of these limitations significantly reduce the dramatic impact of these data.”

“Enfortumab vedotin plus pembrolizumab is poised to become a new standard of care in the perioperative treatment of cisplatin-ineligible or -refusing patients with muscle-invasive bladder cancer,” Dr. Rosenberg concluded.

DISCLOSURE: Dr. Rosenberg reported financial relationships with Acrivon Therapeutics, Aktis Oncology, Araris Biotech, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Clinical Care Options, Clinical Education Alliance, Eli Lilly, EMD Serono, Generate Biomedicines, Gilead Sciences, IDEOlogy Health, Johnson & Johnson, Mashup Media, Medscape, Medistrava, Merck, MJH Life Sciences, Natera, Pfizer, PSL, Roche/Genentech, Research To Practice, Samsung Bioepis, SignifyMD, Touch Oncology, Tyra Biosciences, and UpToDate.