Progress in management of advanced clear-cell renal cell carcinoma

Advanced clear-cell renal cell carcinoma (ccRCC) management has become increasingly complex in the immunotherapy era, particularly with regard to first-line treatment selection and post-immunotherapy sequencing. This review summarizes current evidence on systemic and local treatment strategies, with emphasis on practical decision-making in routine care. A structured PubMed/MEDLINE search (January 2000 to March 2026) was conducted to identify English-language phase II–III trials, large prospective studies, and major guidelines relevant to advanced ccRCC. Current first-line treatment is centered on immune checkpoint inhibitor (ICI)-based combinations. ICI plusVEGFR tyrosine kinase inhibitor (VEGFR-TKI) regimens are generally preferred when rapid disease control is required, whereas dual ICI therapy may be more suitable for selected patients in whom durable benefit and treatment-free intervals are prioritized. VEGFR-TKI monotherapy remains an option when immunotherapy is contraindicated. After prior ICI exposure, VEGFR-TKIs continue to represent the treatment backbone, while later-line options such as hypoxia-inducible factor-2α (HIF-2α) inhibitors and lenvatinib-everolimus further expand sequencing possibilities. Randomized studies have not shown consistent benefit for routine ICI rechallenge in unselected populations. Overall, advanced ccRCC management requires structured individualization, while validated predictive biomarkers and prospective sequencing data remain important unmet needs.