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, randomised, controlled, phase 3 study

Background: In the ongoing EV-302 trial, first-line enfortumab vedotin plus pembrolizumab improved progression-free survival and overall survival versus platinum-based chemotherapy in patients with locally advanced or metastatic urothelial cancer. Patient-reported outcomes (PROs) from EV-302 are reported here. Methods: EV-302 was a phase 3, open-label, two-group, randomised global study to evaluate the combination of enfortumab vedotin plus pembrolizumab versus standard-of-care platinum-based chemotherapy (gemcitabine with cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial cancer. The study was done at 185 clinical sites in 25 countries. Eligible patients were aged 18 years and older with unresectable untreated locally advanced or metastatic urothelial cancer, were eligible for platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were randomly assigned (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 platinum-based chemotherapy consisting of gemcitabine (1000 mg/m2, intravenously) on days 1 and 8 of each cycle plus either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC] 4·5 or 5·0 according to local guidelines) on day 1 of each 3-week cycle for up to six cycles using interactive response technology. Randomisation was stratified by cisplatin eligibility, PD-L1 expression status, and presence or absence of liver metastases. The dual primary endpoints of progression-free survival and overall survival in patients with locally advanced or metastatic urothelial cancer have been reported previously. Here, we report additional, protocol-prespecified secondary endpoint data, and statistical analysis plan-prespecified descriptive endpoints assessing patient quality of life (QOL). These endpoints related to patient functioning and symptoms and were assessed using two PRO questionnaires: the Brief Pain Inventory-Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The PRO full analysis set comprised patients who received study treatment and completed at least one baseline PRO questionnaire. The BPI-SF and the EORTC QLQ-C30 were completed at baseline, weekly for 12 weeks, at week 14, then every 3 weeks during follow-up. Time to pain progression and mean change from baseline in BPI-SF worst pain at week 26 were protocol-prespecified secondary endpoints tested by the hierarchical gatekeeping strategy. Mean change from baseline to week 26 in EORTC QLQ-C30 and BPI-SF scale scores were analysed descriptively. The trial is registered with ClinicalTrials.gov, NCT04223856. Findings: At data cutoff on Aug 8, 2023, 886 patients were enrolled in the study, with a median duration of follow-up for survival of 17·2 months (IQR 12·5–21·7). 731 (83%) of 886 patients completed at least one PRO questionnaire at baseline and were included in the PRO full analysis set, with 376 patients treated with enfortumab vedotin plus pembrolizumab and 355 with platinum-based chemotherapy. 570 (78%) of 731 patients were male, 161 (22%) were female, and 479 (66%) patients were White. There was no significant difference in time to pain progression between treatments; hence differences in least squares mean change in BPI-SF worst pain score from baseline to week 26 with enfortumab vedotin plus pembrolizumab versus platinum-based chemotherapy were not formally tested. However, a numerical improvement from baseline up to week 26 was observed (least squares mean –0·74, SE 0·12 vs –0·36, 0·12; least squares mean difference –0·38, SE 0·13; 95% CI –0·64 to –0·12; nominal two-sided p value 0·0037). Overall least squares mean change in EORTC QLQ-C30 Global Health Status (GHS)/QOL from baseline up to week 26 favoured enfortumab vedotin plus pembrolizumab (least squares mean difference 2·54, 95% CI 0·41–4·67). In patients with moderate to severe baseline pain (worst pain score ≥5) receiving enfortumab vedotin plus pembrolizumab, there were clinically meaningful improvements from baseline up to week 26 in worst pain (least squares mean change: enfortumab vedotin plus pembrolizumab –2·96 [SE 0·22], platinum-based chemotherapy –2·43 [0·21]; least squares mean difference –0·53, 95% CI –1·03 to –0·02; nominal p=0·041) and in EORTC QLQ-C30 GHS/QOL (least squares mean change: enfortumab vedotin plus pembrolizumab 8·88 [1·53], platinum-based chemotherapy 4·11 [1·45]; least squares mean difference 4·77, 95% CI 1·24–8·29; nominal p=0·0083). Interpretation: Enfortumab vedotin plus pembrolizumab significantly improved survival outcomes versus platinum-based chemotherapy without detriment to GHS/QOL, pain, or functioning. Patients with moderate to severe baseline pain had clinically meaningful improvements in worst pain and GHS/QOL with enfortumab vedotin plus pembrolizumab. These data provide further evidence to support the use of enfortumab vedotin plus pembrolizumab as a preferred treatment option for patients with previously untreated locally advanced or metastatic urothelial cancer. Funding: Seagen (acquired by Pfizer in December, 2023), Astellas Pharma, and Merck Sharp & Dohme.