Effect of First-Line Combination Systemic Therapy on Favorable-Risk Clear Cell Renal Cell Carcinoma: A Retrospective Study

<b>Background/Objectives</b>: For patients with advanced or metastatic clear cell renal cell carcinoma (RCC), combinations of immune checkpoint inhibitors (ICIs) and VEGFR-targeted tyrosine kinase inhibitors (TKIs) are standard first-line therapies. However, the clinical benefit of these regimens in patients with favorable IMDC risk remains unclear. <b>Methods</b>: We retrospectively analyzed 147 patients with favorable-risk metastatic RCC treated with first-line systemic therapy at the Samsung Medical Center between 2019 and 2023. Treatment regimens included TKI monotherapy (<i>n</i> = 110) or ICI-TKI combinations (<i>n</i> = 37). Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were evaluated using Kaplan-Meier and Cox regression analyses. <b>Results</b>: At a median follow-up of 46.3 months, the overall median PFS was 20.1 months (95% CI, 14.5-25.7). Median PFS was 26.2 months with ICI-TKI combinations versus 17.0 months with TKI monotherapy (HR 1.32; 95% CI, 0.82-2.12; <i>p</i> = 0.25). In multivariate analysis, TKI monotherapy (HR 14.01; <i>p</i> = 0.002) and liver metastasis (HR 9.17; <i>p</i> < 0.001) were independent predictors of shorter PFS. ORR was significantly higher with combination therapy (68% vs. 46%; <i>p</i> = 0.01). Median OS was not reached in either group, with 3-year OS rates of 89% and 84%, respectively. <b>Conclusions</b>: The findings suggest that even within the favorable-risk population, clinical heterogeneity influences treatment outcomes, emphasizing the need for individualized therapy selection and refined prognostic models.