Enfortumab vedotin in ECOG-PS 2 advanced urothelial carcinoma patients: a real-world study from the ARON-2EV project

BACKGROUND: Enfortumab vedotin (EV) is approved for the treatment of metastatic urothelial carcinoma (mUC), as monotherapy or in combination with immune checkpoint inhibitors (ICIs), following the results of recent practice-changing clinical trials, such as EV-301 and EV-302. However, EV-301 included only patients with Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 0 or 1, while ECOG-PS 2 mUC patients were excluded. OBJECTIVE: In clinical settings, the benefit of EV for this group of vulnerable patients remains a significant and yet unresolved question. The aim of our study was to evaluate the impact of ECOG-PS on survival outcomes in patients treated with EV using the ARON global real-world database. PATIENTS AND METHODS: A total of 483 mUC patients with ECOG-PS 0-1 and 85 with ECOG-PS 2 and treated with EV were included. The coprimary endpoints were Overall Survival (OS) and Progression-Free Survival (PFS) to compare the clinical outcomes of mUC patients with ECOG-PS 2 versus ECOG-PS 0 or 1. The secondary endpoints included the comparison of OS and PFS in these two patient groups according to metastatic sites (liver, bone, lung, lymph nodes, brain, soft tissue). RESULTS: The median OS was 13.63 months (95% CI 11.9-15.57) and 6.34 months (95% CI 4.96-8.48) in mUC patients with ECOG-PS 0-1 and ECOG-PS 2, respectively. Patients with ECOG-PS 2 receiving EV reported statistically significantly shorter OS compared to those with ECOG-PS 0-1 (HR 2.24; 95% CI 1.64-3.06; p < 0.001). The median PFS was 7.39 months (95% CI 6.60-8.04) and 3.98 months (95% CI 3.21-5.95) in mUC patients with ECOG-PS 0-1 and ECOG-PS 2, respectively. Patients with ECOG-PS 2 receiving EV reported statistically significantly shorter PFS compared to those with ECOG-PS 0-1 (HR 1.71; 95% CI 1.29-2.27; p < 0.001). Similarly, shorter OS and PFS was observed in ECOG-PS 2 patients with liver, bone, lung, and lymph nodes metastases, while shorter PFS was associated with lymph nodes and bone metastases. CONCLUSIONS: Our analysis showed worse survival outcomes in pretreated mUC with ECOG-PS 2 receiving EV monotherapy; however, given the retrospective design and baseline imbalances between ECOG groups, these findings should not be interpreted as evidence of reduced intrinsic EV efficacy. The outcomes of EV monotherapy in ECOG-PS 2 patients remains uncertain and can only be inferred from non-randomized prospective trials and studies based on real-world evidence. Further studies and multicentric translational collaborations are fundamental to validate these findings.