First-line therapies analysis in advanced/metastatic urothelial carcinoma: Prognostic insights with propensity score analysis and RNA-seq.

713 Background: The combination of antibody-drug conjugates (ADCs) and immunotherapy has great prospects for first-line treatment of advanced urothelial carcinoma (UC). This study aimed to explore the efficacy, safety, and prognostic biomarkers of disitamab vedotin (DV) combined with a PD-1 inhibitor and compared them with other first-line regimens without DV. Methods: Patients with advanced UC received first-line treatment and were enrolled retrospectively from July 2021 to December 2023 in two cancer centers. Propensity score (PS) matching analysis was used to compare the DV group and the non-DV group. In the DV group, RNA-seq was used to analyze differential expressed genes. Results: A total of 97 patients were included. The 1-year overall survival (OS) and progression-free survival (PFS) rates were 74.4% and 49.7%, respectively. PS score and first-line treatment regimen were independent prognostic factors for both OS and PFS. Survival analysis showed that DV combined with PD-1 inhibitor significantly improved PFS compared with other 3 regimens, including chemotherapy alone (P≤0.01), PD-1 inhibitor plus chemotherapy (P≤0.01), and PD-1 inhibitor alone (P≤0.01). DV combined with PD-1 inhibitor also led to better OS compared to chemotherapy (P≤0.01) or PD-1 inhibitor alone(P≤0.01), with a trend toward improved OS versus PD-1 inhibitor plus chemotherapy (P＝0.129). After PS matching, there were 40 patients, each in the DV group and Non-DV group. There were significant differences between the DV group and Non-DV group in terms of objective response rate (77.5% vs.37.5%, p=0.001), 1-year PFS rate (72% vs.22.2%, p=0.000), and 1-year OS rate (84% vs. 62%, p=0.003). Additionally, differentially expressed genes were identified between patients using DV with PFS >1 year and PFS <1 year and RNA-Seq analysis highlighted enriched pathways such as cytosolic and metabolic pathways, offering potential insights into DV resistance mechanisms. Conclusions: The first-line regimen of DV plus immunotherapy for patients with advanced UC was more effective and safer than the regimen without DV.