A perioperative regimen of the antibody-drug conjugate enfortumab vedotin-ejfv plus the PD-1 inhibitor pembrolizumab significantly improved event-free survival, overall survival, and pathological complete response rates compared to radical cystectomy alone in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for or declined cisplatin-based chemotherapy. The data were presented at the 26th Annual Meeting of the Society of Urologic Oncology (SUO).¹

Results from the pivotal phase III KEYNOTE-905 study (ClinicalTrials.gov identifier NCT03924895) demonstrated a significant improvement in clinical outcomes, with median overall survival not yet reached in the enfortumab vedotin plus pembrolizumab arm compared to 41.7 months in the control arm (hazard ratio [HR] = 0.50). Furthermore, the pathological complete response rate with the combination reached 57.1% vs 8.6% observed with surgery alone.

“We’re proud to report that KEYNOTE-905 is the first phase III study to show improved efficacy with perioperative therapy relative to surgery for patients who are cisplatin-ineligible,” said lead study author Hristos Kaimakliotis, MD, Associate Professor of Urology at Indiana University School of Medicine. “This treatment option represents a new standard of care in this population with a high unmet clinical need, and [the treatment regimen] was recently approved by the U.S. Food and Drug Administration.”

Cisplatin-Ineligible MIBC

As Dr. Kaimakliotis explained, radical cystectomy plus pelvic lymph node dissection is the established standard for MIBC. However, nearly one-half of patients with MIBC are ineligible for cisplatin-based chemotherapy due to comorbidities such as renal impairment, cardiac issues, or poor performance status (up to 14.9% of patients in this trial had an Eastern Cooperative Oncology Group [ECOG] performance status of 2). These cisplatin-ineligible patients, who are often older (median age = 73–74 years) and frailer, have historically lacked effective neoadjuvant treatment options and face poorer outcomes with surgery alone. This study highlights a critical unmet medical need, said Dr. Kaimakliotis.

The combination of enfortumab vedotin, an antibody-drug conjugate targeting nectin-4, and pembrolizumab presented a strong rationale for investigation in this setting, having shown robust activity in metastatic urothelial carcinoma (EV-302 trial).²

KEYNOTE-905 Study Design

The KEYNOTE-905 study was a global, open-label, randomized phase III trial. Eligible adult patients had MIBC (clinical stage T2–T4aN0M0 or T1–T4aN1M0) of predominant urothelial histology, who were either cisplatin-ineligible or declined cisplatin. Cisplatin ineligibility was determined per modified Galsky criteria, ie, ECOG 2 or Karnofsky performance status < 60% to 70%, creatinine clearance < 60 mL/min, NYHA class III heart failure, grade ≥ 2 hearing loss, and/or grade ≥ 2 peripheral neuropathy. Patients were randomized 1:1 to receive either perioperative enfortumab vedotin plus pembrolizumab or radical cystectomy plus pelvic lymph node dissection only (control arm).

Study Details

The experimental arm consisted of treatment with 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 six cycles of adjuvant enfortumab vedotin plus 14 cycles of adjuvant pembrolizumab. Treatment continued until disease progression, unacceptable adverse events, withdrawal of consent, or completion of planned treatment.

The primary endpoint was event-free survival by blinded independent central review, with key secondary endpoints including overall survival and pathological complete response rate.

A total of 344 patients were randomized (170 to enfortumab vedotin plus pembrolizumab and 174 to the control arm). Median study follow-up was 25.6 months. Baseline characteristics were well balanced between the arms. Over 80% of patients were cisplatin-ineligible. More than 75% of patients had a clinical stage of T3–T4a, as determined by a combination of central pathology and imaging for baseline TNM staging.

Efficacy Across All Endpoints

As Dr. Kaimakliotis reported, the enfortumab vedotin plus pembrolizumab combination significantly improved event-free survival, with median event-free survival not reached for the treatment arm vs 15.7 months for the control arm (HR = 0.40, one-sided P < .0001). There was an early and sustained separation of the event-free survival curves.

Similarly, median overall survival was not reached for the treatment arm vs 41.7 months for the control arm (HR = 0.50, one-sided P = .0002).

“This represents the first phase III trial to demonstrate an overall survival benefit for perioperative therapy in this challenging patient population,” said Dr. Kaimakliotis, who noted that both event-free and overall survival benefits were consistent across key subgroups, including age, ECOG performance status, PD-L1 status, and tumor stage.

The pathological complete response rate was significantly improved, from 8.6% in the control arm to 57.1% in the enfortumab vedotin plus pembrolizumab arm (estimated difference 48.3%, one-sided P < .000001). This was considered a conservative estimate, as patients who declined cystectomy after achieving a clinical complete response were counted as nonresponders. An exploratory analysis indicated that event-free survival benefits were observed irrespective of achieving a pathological complete response rate.

Importantly, the combination regimen did not impact the ability of patients to undergo curative-intent surgery or delay time to the operating room. Eighty-seven percent (87.6%) of patients in the enfortumab vedotin plus pembrolizumab arm and 89.7% in the control arm proceeded to surgery.

Safety Profile

The overall safety profile of enfortumab vedotin plus pembrolizumab was manageable and consistent with prior experience of this regimen in the metastatic setting. Any-grade treatment-emergent adverse events occurred in 100% of patients in the enfortumab vedotin arm (71.3% grade 3 or higher) vs 64.8% in the control arm (45.9% grade 3 or higher). Serious treatment-emergent adverse events occurred in 58.1% of the enfortumab vedotin arm vs 40.9% of the control arm.

Adverse events leading to surgical delay were 4.0% vs 0.6%, and adverse events during the surgical phase, including serious adverse events and those leading to death (7.8% vs 5.7% overall treatment-emergent adverse events leading to death, with two treatment-related deaths occurring in the neoadjuvant phase of the experimental arm), were similar between both arms, suggesting a low impact of the combination on worsening surgical complications.

“The safety profile of perioperative enfortumab vedotin plus pembrolizumab was manageable and consistent with prior reports of this regimen in the locally advanced or metastatic urothelial carcinoma setting,” said Dr. Kaimakliotis. “No new safety signals were observed.”

The KEYNOTE-B15 study (NCT04700124) is ongoing to investigate perioperative enfortumab vedotin plus pembrolizumab in the cisplatin-eligible population.

Disclosures: Dr. Kaimakliotis reported financial relationships with Pfizer and Astellas.

References

1. Kaimakliotis HZ, Shore N, Adra N, et al: Primary efficacy and surgical details in KEYNOTE-905: Neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin ineligible. 2025 SUO Annual Meeting. Presented December 5, 2025.
2. Powles T, Vladerrama BP, Gupta S, et al: Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med 390:875-888, 2024.