Top: Overall survival (OS) achieved with current approved treatment options. VEGFR inhibitors used up-front for advanced or metastatic ccRCC result in a median OS of <30 mo. The median OS for the combination of nivolumab and the CTLA-4 blocker ipilimumab has not been reached yet (FDA approved for intermediate or poor-risk advanced ccRCC). At time of disease progression, an ICB or a different VEGFR inhibitor is indicated. The combination of a VEGFR inhibitor with an mTOR inhibitor (lenvatinib and everolimus) is also an approved treatment option following one prior anti-angiogenic therapy. Bottom: ORR achieved with experimental or approved treatment options for untreated advanced or metastatic renal cancer. The ORRs achieved with the combination of a VEGFR inhibitor with an ICB are consistently >50%, although these are reported from relatively small phase 1 studies, and phase 3 randomized studies testing such combinations versus sunitinib are ongoing. CTLA-4, cytotoxic T lymphocyte–associated protein 4.