Perioperative Enfortumab Vedotin Plus Pembrolizumab Does Not Compromise QOL in Cisplatin-Eligible MIBC

Perioperative treatment with enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) was not associated with a clinically meaningful detriment in general or cystectomy-specific health-related quality of life (HRQOL) compared with neoadjuvant gemcitabine and cisplatin in patients with cisplatin-eligible muscle-invasive bladder cancer (MIBC), according to a prespecified patient-reported outcome (PRO) analysis of the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124) presented at the 2026 ESMO Congress.¹

No clinically meaningful between-arm differences emerged in any of the 6 prespecified HRQOL domains, and the steepest declines in both arms occurred after radical cystectomy.

Findings showed that at postsurgery week 42, the least squares (LS) mean change from baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (EORTC QLQ-C30) global health status (GHS)/QOL score was –1.58 (95% CI, –3.54 to 0.38) in the enfortumab vedotin/pembrolizumab arm (n = 403) vs –2.43 (95% CI, –4.45 to –0.41) in the chemotherapy arm (n = 394), translating to an LS mean difference of 0.85 (95% CI, –1.74 to 3.44). The respective LS mean changes in physical functioning were –5.42 (95% CI, –7.24 to –3.61) and –6.28 (95% CI, –8.16 to –4.40; LS mean difference, 0.86; 95% CI, –1.73 to 3.45), and in role functioning were –9.56 (95% CI, –12.50 to –6.63) and –9.35 (95% CI, –12.40 to –6.31; LS mean difference, –0.21; 95% CI, –4.31 to 3.88). None of these declines crossed the minimal important difference of a 10-point or greater worsening from baseline.

“We believe that, together with efficacy and safety results from the primary analysis, these PRO findings further support the overall benefit-risk profile of perioperative enfortumab vedotin plus pembrolizumab in patients with cisplatin-eligible MIBC,” lead study author Alfonso Gómez de Liaño, MD, of Complejo Hospitalario Universitario Insular-Materno Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, in Spain, said in the presentation.

Prior data from KEYNOTE-B15 supported the FDA approval of pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex), each in combination with enfortumab vedotin, as neoadjuvant treatment followed by adjuvant treatment following cystectomy in adult patients with MIBC.²

How was KEYNOTE-B15 designed?

The open-label phase 3 trial enrolled adult patients with MIBC of clinical stage T2-T4aN0M0 or T1-T4aN1M0 by central assessment, at least 50% urothelial histology, eligibility for radical cystectomy and pelvic lymph node dissection (RC + PLND), no Galsky criteria for cisplatin ineligibility, and an ECOG performance status of 0 or 1.¹

Patients were randomly assigned 1:1 to receive 4 cycles of neoadjuvant enfortumab vedotin at 1.25 mg/kg on days 1 and 8 plus pembrolizumab at 200 mg on day 1 of each 21-day cycle, followed by RC + PLND and then 5 cycles of adjuvant enfortumab vedotin plus 13 cycles of adjuvant pembrolizumab (n = 405); or 4 cycles of neoadjuvant cisplatin at 70 mg/m² on day 1 plus gemcitabine at 1000 mg/m² on days 1 and 8 of each 21-day cycle, followed by RC + PLND and observation (n = 403). Randomization was stratified by PD-L1 status (combined positive score ≥10 vs <10), clinical stage, and geographic region.

ADDITIONAL ESMO 2026 COVERAGE of KEYNOTE-B15: Perioperative Enfortumab Vedotin Plus Pembrolizumab Improves ctDNA Clearance in Cisplatin-Eligible MIBC

In the primary analysis, enfortumab vedotin plus pembrolizumab significantly improved event-free survival (HR, 0.53; 95% CI, 0.41-0.70; P < .001) and overall survival (HR, 0.65; 95% CI, 0.48-0.89; 2-sided P = .006), as well as pathologic complete response rate (P < .001), vs neoadjuvant chemotherapy.

Change from baseline to postsurgery week 42 and time to definitive deterioration (TTD) in EORTC QLQ-C30 GHS/QOL, physical functioning, and role functioning, as well as Bladder Cancer Index (BCI) urinary, bowel, and sexual scores, were prespecified secondary end points. The PRO analysis population included all randomly assigned patients who received at least 1 dose of study treatment and had at least 1 PRO assessment for the given end point. PROs were collected throughout the neoadjuvant and postsurgery phases. The median time from randomization to the October 27, 2025, data cutoff was 33.6 months (range, 22.5-53.6).

What did the bladder-specific analysis show?

At postsurgery week 42, the LS mean change from baseline in BCI urinary score was –0.77 (95% CI, –3.02 to 1.48) in the enfortumab vedotin/pembrolizumab arm (n = 402) vs –3.51 (95% CI, –5.81 to –1.21) in the chemotherapy arm (n = 394; LS mean difference, 2.74; 95% CI, –0.15 to 5.63). BCI bowel score changes were –1.86 (95% CI, –3.63 to –0.10) and –2.07 (95% CI, –3.88 to –0.25), respectively (LS mean difference, 0.20; 95% CI, –2.16 to 2.57).

BCI sexual scores worsened by –15.13 (95% CI, –17.79 to –12.46) in the enfortumab vedotin/pembrolizumab arm (n = 401) and –14.82 (95% CI, –17.57 to –12.06) in the chemotherapy arm (n = 390), crossing the 7-point minimal important difference in both arms, with an LS mean difference of –0.31 (95% CI, –3.77 to 3.15).

Over time, the largest declines across EORTC QLQ-C30 and BCI domains occurred after surgery, followed by partial recovery in both arms, with largely overlapping postoperative trajectories. Sexual function did not recover after surgery, which Gómez de Liaño noted is consistent with the known impact of radical cystectomy, “a major life-changing surgery.”

Did time to definitive deterioration differ between arms?

TTD did not differ significantly between arms in any domain, and all HR confidence intervals crossed 1. In the EORTC QLQ-C30, definitive deterioration occurred in 20.6% vs 22.8% of patients in the enfortumab vedotin/pembrolizumab and chemotherapy arms, respectively, for GHS/QOL (HR, 0.84; 95% CI, 0.61-1.14); 24.0% vs 25.5% for physical functioning (HR, 0.88; 95% CI, 0.66-1.18); and 28.2% vs 32.9% for role functioning (HR, 0.80; 95% CI, 0.61-1.04). Median TTD was not reached in either arm for these domains.

For the BCI, definitive deterioration rates were 24.8% vs 25.1% for urinary score (HR, 0.93; 95% CI, 0.70-1.25) and 26.6% vs 22.7% for bowel score (HR, 1.11; 95% CI, 0.83-1.49). For sexual score, 45.8% vs 39.0% of patients experienced definitive deterioration, with a median TTD of 25.5 months (95% CI, 18.9-33.5) vs 44.3 months (95% CI, 24.7-not reached; HR, 1.17; 95% CI, 0.94-1.47).

References

1. Gómez de Liaño A, Perez Valderrama B, Maruzzo M, et al. Health-related quality of life with neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer eligible for cisplatin in the phase 3 KEYNOTE-B15 study. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 4738RO.
2. FDA approves pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph each with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. July 10, 2026. Accessed October 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph-each-enfortumab-vedotin