Metastatic Renal Cell Carcinoma — Clear Cell

Sequencing for metastatic clear-cell renal cell carcinoma: IMDC risk-stratified first-line immunotherapy (nivolumab + ipilimumab for intermediate/poor risk, or an immunotherapy + tyrosine-kinase-inhibitor doublet across risk groups), followed by single-agent VEGF-directed tyrosine kinase inhibition and later HIF-2α inhibition.

IMDC prognostic risk group?

1L: Immunotherapy + TKI (pembrolizumab + axitinib, pembrolizumab + lenvatinib, or nivolumab + cabozantinib)

Preferred for favorable-risk disease and an option across all risk groups, especially when a rapid response is needed for high tumor burden or symptoms. Monitor for immune-related adverse events plus TKI hypertension, hand-foot syndrome, and proteinuria.

Evidence: KEYNOTE-426 · CLEAR · CheckMate 9ER

1L: Nivolumab + ipilimumab

Preferred for intermediate- and poor-risk disease, offering durable responses and a treatment-free survival tail. Monitor closely for immune-related toxicity; ipilimumab is given for four induction doses, then nivolumab maintenance.

Evidence: CheckMate 214

2L: Single-agent VEGFR TKI (cabozantinib) or lenvatinib + everolimus

Both first-line options here are immunotherapy-based, so second line is VEGFR-directed: cabozantinib monotherapy (preferred) or lenvatinib + everolimus. Reserve nivolumab (CheckMate-025) for the uncommon patient who received TKI-only first-line therapy.

3L+: Belzutifan (HIF-2α inhibitor) or an alternate VEGFR TKI

Belzutifan is approved after prior immunotherapy and antiangiogenic therapy; monitor for anemia and hypoxia. Sequence remaining VEGFR TKIs and consider a clinical trial.