Background
Urothelial cancer, commonly affecting the bladder and urinary tract, can become locally advanced or metastatic, presenting significant treatment challenges. The EV-302 trial investigated the efficacy of combining enfortumab vedotin, an antibody-drug conjugate targeting nectin-4, with pembrolizumab, an immune checkpoint inhibitor, compared to standard platinum-based chemotherapy (cisplatin or carboplatin with gemcitabine) in previously untreated patients. Prior results demonstrated improved progression-free survival (PFS) and overall survival (OS) with the combination therapy.
Beyond survival metrics, understanding patient-reported outcomes (PROs) such as pain, symptoms, and quality of life (QOL) is critical for holistic treatment evaluation. This report presents PRO data from the EV-302 trial, assessing how patients perceived their wellbeing and symptom burden during treatment.
Methods
EV-302 was a global, open-label phase 3 randomized study conducted at 185 sites across 25 countries. Eligible participants were adults with unresectable, previously untreated locally advanced or metastatic urothelial cancer, suitable for platinum-based chemotherapy, and with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Participants were randomized 1:1 to receive either:
- Enfortumab vedotin (1.25 mg/kg intravenously on days 1 and 8 of 3-week cycles) plus pembrolizumab (200 mg intravenously on day 1 of each cycle), or
- Standard platinum-based chemotherapy: gemcitabine (1000 mg/m2 intravenously on days 1 and 8) plus cisplatin (70 mg/m2) or carboplatin (AUC 4.5 or 5.0 per local guidelines) on day 1 of each 3-week cycle, up to six cycles.
Randomization was stratified by cisplatin eligibility, PD-L1 expression, and liver metastases presence.
Patient functioning and symptom assessments used two validated PRO questionnaires:
- Brief Pain Inventory-Short Form (BPI-SF): measures pain severity and interference.
- European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30): evaluates multiple domains of quality of life including global health status.
PROs were collected at baseline, weekly for 12 weeks, at week 14, then every 3 weeks during follow-up. Key secondary endpoints included time to pain progression and mean change in worst pain at week 26. Statistical analysis followed a hierarchical gatekeeping strategy, with descriptive analyses of QOL score changes.
Findings
At data cutoff (August 8, 2023), 886 patients were enrolled, with median survival follow-up of 17.2 months. Of these, 731 (83%) completed at least one baseline PRO questionnaire and formed the PRO full analysis set: 376 received enfortumab vedotin plus pembrolizumab, and 355 received platinum-based chemotherapy. The cohort was predominantly male (78%) and White (66%).
No significant difference was observed between treatment groups in time to pain progression, so formal hypothesis testing for worst pain change was not conducted. However, numerical improvements favored the enfortumab vedotin plus pembrolizumab arm, with a least squares mean decrease from baseline to week 26 in worst pain score of -0.74 compared to -0.36 for chemotherapy (difference -0.38; 95% CI -0.64 to -0.12; p=0.0037).
Quality of life, as measured by EORTC QLQ-C30 global health status (GHS)/QOL, also favored the combination therapy with a mean difference of 2.54 (95% CI 0.41 to 4.67) at week 26.
In patients presenting with moderate to severe baseline pain (worst pain score ≥5), clinically meaningful improvements were seen with enfortumab vedotin plus pembrolizumab compared to chemotherapy, both in worst pain (mean change -2.96 vs -2.43; difference -0.53; 95% CI -1.03 to -0.02; p=0.041) and GHS/QOL (mean change 8.88 vs 4.11; difference 4.77; 95% CI 1.24 to 8.29; p=0.0083).
Interpretation
The combination of enfortumab vedotin plus pembrolizumab not only significantly improves survival outcomes in previously untreated locally advanced or metastatic urothelial cancer patients but also maintains or improves patient-reported quality of life and pain control compared to standard platinum-based chemotherapy. Particularly, patients with more severe baseline pain experienced meaningful symptom relief and better overall QOL with the combination therapy.
These findings support enfortumab vedotin plus pembrolizumab as a preferred first-line treatment option, offering both clinical efficacy and patient-centered benefits.
Funding and Conflicts of Interest
The study was funded by Seagen (acquired by Pfizer in December 2023), Astellas Pharma, and Merck Sharp & Dohme.
Reference
Gupta S, Loriot Y, Van der Heijden MS, et al. Enfortumab vedotin plus pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (EV-302): patient-reported outcomes from an open-label, randomized, controlled, phase 3 study. Lancet Oncol. 2025 Jun;26(6):795-805. doi:10.1016/S1470-2045(25)00158-5. PMID: 40449498.
