Exploring skin toxicity as a predictor of response in urothelial carcinoma patients treated with enfortumab vedotin: A meta-analysis of Kaplan-Meier reconstructed individual patient data.

Abstract

e16555 Background: Skin toxicity (ST) emerged as an on-target toxicity related to enfortumab vedotin (EV), mainly occurring in the first treatment cycle. Although EV prolonged clinical response in urothelial carcinoma (UC) setting, no reliable biomarkers have been well established to predict therapeutic response. We aimed to evaluate whether ST could predict clinical response in UC patients undergoing EV therapy. Methods: A study-level (SLMA) and reconstructed individual patient data (rIPDMA) meta-analysis from Kaplan-Meier (KM) survival data was conducted. Systematic searches in Pubmed, Embase, Cochrane databases, and ASCO, ESMO, and AUA conference databases up to September 2024 identified studies comparing overall survival (OS) and progression-free survival (PFS) between UC patients treated with EV with and without ST. Survival data were extracted from published KM curves. A mixed-effects Cox proportional hazards model or flexible parametric model (FPM) was applied based on proportional hazards assumption testing. Landmark analysis (LA) was conducted to assess survival outcomes. All statistical analyses were performed using R (version 4.4.1). Results: Five retrospective studies, with 310 patients, were analyzed. In the SLMA, ST was significantly associated with improved OS (HR: 0.56; 95% CI: 0.40–0.79; p < 0.01), though PFS differences were non-significant (HR: 0.86; 95% CI: 0.60–1.23; p = 0.41). The rIPDMA of four studies showed the ST group had a 60% lower hazard of death compared to the control group (CT) (HR: 0.40, 95% CI: 0.28-0.58, p < 0.01), with KM curves indicating a sustained survival benefit. FMP-based analysis showed improved PFS in the ST group (HR: 0.64;95% CI: 0.47-0.88, p < 0.05). LA revealed no significant PFS differences beyond 5 months (HR: 1.3, 95% CI: 0.79-2.15), but within the 0-5 month window, ST was associated with better PFS (HR: 0.35; 95% CI: 0.22-0.56). These findings emphasize early survival benefits in patients with ST. Conclusions: ST was significantly associated with better OS, highlighting its potential as a biomarker for clinical response. Further research is needed to validate these findings, particularly through randomized prospective studies involving larger patient populations. Pooled analysis from reconstructed individual patient data reporting overall survival (OS) and progression-free survival (PFS). Author OS (HR 95% CI) PFS (HR 95% CI) Furubayashi, 2024 0.68 (0.31-1.53) p=0.35 1.14 (0.63-2.06) p=0.67 Nakane, 2024 0.43 (0.19-0.96) p=0.04 N/A Seeman, 2024 N/A N/A Vlachou, 2024 0.31 (0.17-0.56) p<0.01 0.36 (0.22-0.6) p<0.01 Yamamoto, 2024 0.35 (0.16-0.74) p<0.01 0.78 (0.43-1.39) p=0.39 Pooled analysis 0.4 (0.28-0.58) p<0.05 0.64 (0.47-0.88) p<0.05 N/A - Not available. CI - Confidence interval.