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

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.

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.

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).

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.

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.