Optimizing systemic therapy for metastatic renal cell carcinoma beyond the first-line setting

•Single agents that target VEGFR (axitinib) and mTOR (everolimus) are standards in metastatic RCC.•Immune checkpoint inhibitors and drugs that target mechanisms of resistance to VEGFR inhibitors (Dual VEGFR/MET inhibitors) are likely to revolutionize mRCC management.•Sequencing, rather than combination drugs, will remain a standard at least in the near future.

The introduction of molecularly targeted therapies (TTs) has transformed the management of metastatic renal cell carcinoma (mRCC). Within a relatively short period of time, systemic treatment of mRCC has evolved from a disease treated only by cytokines to a disease where TT is the cornerstone of patient management.Since the approval of sorafenib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), in December 2005, 7 drugs have been introduced that have provided a high level of clinical efficacy in patients with mRCC, with a median survival of ~30 months in an unselected patient population that generally fits trials eligibility. Despite such success, advancements in therapies have reached a plateau: different combinations of targeted agents have not demonstrated additional benefit mainly owing to toxicity concerns, and some novel agents have failed to show benefit over approved drugs in clinics.In this review, we aim to focus on optimizing selection of agents in mRCC after progression on first-line TT. We also review how new drugs may transform existing guidelines and break through the current plateau reached with approved agents.