First-Line Treatment for Intermediate and Poor Risk Advanced or Metastatic Clear Cell Renal Cell Carcinoma

Current approved combination treatment regimens all demonstrated improved PFS and OS over VEGFR TKI monotherapy. Standard of care treatment in IMDC intermediate and poor risk disease includes PD-1 plus CTLA-4 or PD-1 plus VEGFR TKI, but no current head-to-head trials between the approved regimens are being conducted. For most patients, the choice of whether to combine PD-1 blockade with CTLA-4 blockade or a VEGFR TKI should involve shared decision making to navigate the need for a response in the short term (ICI/VEGF combinations) and potential durable response and/or treatment free survival (favoring anti-CTLA-4). Ongoing trials of novel triplet combination regimens are using modern comparator arms instead of sunitinib: for example, MK6482 to 012 with pembrolizumab plus lenvatinib, or COSMIC-313 with ipilimumab plus nivolumab. Novel combinations being studied incorporate radiation, surgery, and new therapeutic targets, which may alter our current first-line treatment paradigm. In summary, the inherent tradeoff between long-term outcomes and toxicitywith ICI combinations is a shared decision when choosing among first-line therapy options. Current risk models to direct therapy are still relevant but need to be improved by incorporating prognostic genomic and molecular information.