Effect of censorship in the interpretation of outcomes of the enfortumab vedotin plus pembrolizumab EV-302 phase 3 randomized clinical trial.

Abstract

781 Background: The purpose of this study was to assess whether the high treatment discontinuation rate in the chemotherapy arm of the EV-302 trial could bias survival outcomes. The EV-302 trial demonstrated very significant overall survival (OS) benefit for the Enfortumab Vedotin plus Pembrolizumab (EVP) relative to standard chemotherapy (CHT) for patients with metastatic urothelial carcinoma. However, questions have been raised regarding the high rate of treatment discontinuation in the CHT arm for reasons unrelated to adverse events or progression (33% vs. 10% with EVP, P < .01), potentially resulting in loss of unaccounted information, or informative censoring, and affecting survival results interpretation. Methods: We performed a multistep analysis to assess the impact of differential dropout on trial outcomes. First, Kaplan–Meier (KM) curves were reconstructed from published data to estimate time-to-event outcomes. Second, a reverse KM analysis was conducted to evaluate censoring patterns in the overall population and key subgroups (PD-L1 expression; cisplatin eligibility). Third, simulation models were employed to test whether informative censoring could negatively impact survival benefit by EVP. Results: No significant imbalance in censoring between the treatment arms of EV-302 was found on reverse KM analysis when assessing OS ( P = .73). However, a significant difference was noted for progression-free survival (PFS) ( P = .002). Conclusions: Simulation analysis revealed that even under extreme assumptions of informative censoring, the OS benefit of EVP remained statistically significant. Despite the high discontinuation rate in the CHT arm, OS benefit with the treatment EVP group remains robust. These findings support the reliability of EVP as a first-line treatment in metastatic urothelial carcinoma.