Current and emerging first-line systemic therapies in metastatic clear-cell renal cell carcinoma.

The treatment of metastatic clear-cell renal cell cancer (mccRCC) has seen substantial progress over the last decade. Until 2006, non-specific immunotherapy with high dose interleukin-2 (HD IL-2) was considered as standard therapy of mccRCC. The transition from cytokine to targeted therapy, and now to novel immunotherapeutic agents, significantly increased the overall survival (OS) of patients with mccRCC. Currently, 7 targeted agents and the combination of nivolumab/ipilimumab (immune checkpoint inhibitors, ICIs) have been approved as first-line therapy for mccRCC. Based on evidence from randomized phase III clinical trials, sunitinib and pazopanib (Tyrosine kinase inhibitors of vascular endothelial growth factor; VEGF-TKIs) are the most effective first-line options, especially in favorable and indermediate risk patients. Nivolumab/ipilimumab (dual checkpoint inhibitors) seem to be the preferred first-line therapy in poor-risk patients, although cabozantinib, temsirolimus, sunitinib and pazopanib are also recommended. HD IL-2 remains a reasonable first-line treatment option in selected, favorable-risk younger patients with good performance status. Based on data of previous phase I and II studies, several phase III trials investigating the efficacy and safety of the combination of ICI/VEGF-TKI versus sunitinib in untreated mccRCC are currently underway. These emerging therapies include the combinations of pembrolizumab/lenvatinib, pembrolizumab/axitinib, avelumab/axitinib and atezolizumab/ bevacizu-mab and seem to introduce the mccRCC therapy in a new auspicious era. Moreover, emerging new targeted therapies and other, beyond ICIs, immunotherapies are currently underway.