Treatment of Refractory Metastatic Renal Cell Carcinoma

First-line treatment for metastatic renal cell carcinoma (mRCC) rapidly shifted in recent years with the advent of combination therapies, including immune checkpoint inhibitor (ICI) doublets and combinations of an ICI with a vascular endothelial growth factor receptor (VEGFR) targeted tyrosine kinase inhibitor (TKI). Despite improvements in overall survival and many durable responses, there exists a significant number of patients who fail to respond to these agents, and many patients eventually progress. Given the rapid changes in the front-line setting, it is essential to understand treatment options in refractory mRCC. Here, we review the evidence behind current options for later-line therapies, often involving additional VEGFR-TKIs alone or in combination with mammalian target of rapamycin (mTOR) targeted agents, as well as situations where consideration of immunotherapy rechallenge may be appropriate. Additionally, we describe ongoing clinical trials examining concurrent ICI and TKI in the refractory setting, as well as those studying novel agents, such as targeted drug-antibody conjugates and hypoxia inducible factor 2α (HIF-2α) inhibitors. Finally, we review considerations for non-clear cell histologies in the refractory setting and mechanisms of resistance in mRCC.