The Transition From Sunitinib Monotherapy to Modern First-Line Tyrosine Kinase Inhibitor (TKI)-Containing Regimens in Metastatic Clear-Cell Renal Cell Carcinoma.

Sunitinib historically served as a standard first-line treatment for metastatic clear-cell renal cell carcinoma (RCC), but its contemporary use is limited by inferior efficacy compared with several modern combination regimens, together with cumulative toxicity and acquired resistance. Newer tyrosine kinase inhibitor (TKI)-based treatments have emerged as alternatives, demonstrating improved efficacy but also substantial and regimen-specific toxicity burdens. Contemporary treatment recommendations now favor modern first-line regimens over sunitinib for most patients with advanced or metastatic clear-cell RCC. This review evaluates the clinical evidence supporting the transition from sunitinib monotherapy to contemporary first-line TKI-containing regimens. PubMed and Embase were searched for clinical trials evaluating sunitinib compared with contemporary first-line TKI-based or TKI-containing regimens in previously untreated advanced or metastatic clear-cell RCC. Twenty-two records were identified through database searching, and one additional publication was identified during peer review. After removal of five duplicates, 18 records were screened. Ten publications representing six unique clinical trials met the eligibility criteria and were included in the qualitative synthesis. Extracted data included study design, patient population, treatment arms, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events (AEs). Across the included publications, TKI-containing first-line regimens consistently improved PFS compared with sunitinib. Cabozantinib improved median PFS compared with sunitinib in intermediate- or poor-risk advanced clear-cell RCC [8.6 vs. 5.3 months; hazard ratio (HR) 0.48]. Nivolumab plus cabozantinib improved median PFS [16.6 vs. 8.3 months; HR 0.51] and ORR (55.7% vs. 27.1%). Pembrolizumab plus axitinib improved 12-month OS (89.9% vs. 78.3%; HR 0.53), median PFS (15.1 vs. 11.1 months; HR 0.69), and ORR (59.3% vs. 35.7%). Lenvatinib plus pembrolizumab demonstrated durable benefit in CLEAR, with median PFS of 23.9 versus 9.2 months (HR 0.47), ORR of 71.3% versus 36.7%, and a final OS HR of 0.79. Benmelstobart plus anlotinib also improved median PFS (19.0 vs. 9.8 months; HR 0.53) and ORR (72% vs. 25%). OS benefit varied across trials, while high-grade adverse events were common, with safety definitions differing across studies. The included evidence supports the transition away from sunitinib as the preferred first-line treatment for most patients with advanced or metastatic clear-cell RCC. However, sunitinib remains an evidence-based option for selected patients, including those with contraindications to immune-checkpoint inhibition, some patients with favorable-risk disease, and those with limited access to combination therapy.