Survival Trends in Metastatic Renal Cell Carcinoma Across Therapeutic Eras and Histologic Subtypes

Introduction Immune checkpoint inhibitors have transformed the treatment of metastatic renal cell carcinoma (RCC). Whether these advances translated into population-level survival improvements across histologic subtypes remains uncertain. Materials and methods We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database (2006-2022). Patients older than 20 years with distant-stage RCC were categorized into a targeted therapy era (2006-2015) and an immunotherapy era (2016-2022). Overall survival (OS) and cancer-specific survival (CSS) were evaluated using Kaplan-Meier analysis, restricted mean survival time (RMST) analysis (τ=36 months), and multivariable Cox models adjusting for demographic and clinical variables. The interaction between treatment era and histologic subtype was assessed. Sensitivity analyses were restricted to clear cell RCC. Results Among 7,356 patients, 5,814 (79.0%) were diagnosed during the targeted therapy era and 1,542 (21.0%) during the immunotherapy era, median OS improved from 13 months (95% CI: 13-14) to 17 months (95% CI: 15-19), and median CSS improved from 14 months (95% CI: 14-15) to 19 months (95% CI: 17-21) (both p<0.001). Diagnosis during the immunotherapy era was associated with improved OS (HR: 0.80, 95% CI: 0.76-0.86) and CSS (HR: 0.77, 95% CI: 0.73-0.83). At 36 months, RMST demonstrated absolute gains of 1.82 months for OS and 1.99 months for CSS (both p<0.001). Survival benefit was attenuated in papillary and chromophobe RCC but remained consistent in clear cell RCC. Conclusions Diagnosis during the immunotherapy era was associated with survival improvement in metastatic RCC, predominantly driven by clear cell histology, reinforcing the need for subtype-specific approaches in non-clear cell RCC.