Discrepancies in the administration of sequential therapies for metastatic renal cell carcinoma: Real-world practice versus randomized controlled trials.

481 Background: While randomized controlled trials (RCTs) have established first-line standards for metastatic renal cell carcinoma (mRCC), real-world practice often differs. The use of sequential therapy after first-line treatment remains underexplored. We conducted this study to compare the administration rates of second-line therapy in mRCC between pivotal RCTs and real-world data, and to evaluate their association with overall survival (OS). Methods: Six phase III RCTs (CheckMate-214, COSMIC-313, JAVELIN Renal-101, KEYNOTE-426, CheckMate-9ER, and CLEAR) were compared with real-world data from the Japanese AGEHA database (n = 518). Patients who discontinued first-line therapy due to progression or adverse events (PD/AE) were assessed for the subsequent use of second-line treatment or best supportive care. Age and IMDC risk differences were also evaluated. Survival analysis was performed based on sequential systemic therapy status. Results: Despite younger age and lower IMDC risk in RCTs, some trials showed lower second-line rates than RW. Immune-oncology (IO)-based regimens in real-world practice achieved 55.4%, exceeding rates in nivolumab+cabozantinib (44.1%) and pembrolizumab+lenvatinib (55.5%) trial arms. In real-world, second-line therapy was associated with longer OS after PD/AE (median 43.5 vs 15.1 mo.; p < 0.001). Limitations include possible selection bias and differences in definitions between datasets. Conclusions: Some RCTs reported lower sequential systemic therapy rates than RW practice despite favorable patient selection. In real-world settings, receiving second-line therapy was strongly associated with improved survival, highlighting the need to bridge this gap in future treatment strategies.