Targeted therapy for renal cell carcinoma: focus on 2nd and 3rd line.

INTRODUCTION: Second- and third-line treatments are more and more frequently administered to metastatic renal cell carcinoma (mRCC) patients. AREAS COVERED: Here we discuss the various levels of evidence supporting presently available recommendations, trying to address a number of as yet unanswered issues, and also to take a glowing glance at the future. To do this, we interrogated the Medline database, as well as the proceedings of the main Oncological and Urological conferences for relevant studies. EXPERT OPINION: Until recently, with regard to choosing the second line treatment after the failure of therapy with vascular endothelial growth factor receptors-tyrosine kinase inhibitors (VEGFR-TKIs), the continued inhibition of the VEGF/VEGR pathway, or else the switch to an mTOR inhibitor, is recommended. These two options are characterized by partly different targets, completely different toxicity profiles, but a comparable efficacy. This scenario will change soon, after the publication of two randomized, controlled, phase III trials in which cabozantinib and nivolumab proved to be superior as compared to everolimus. As regards third line treatment, where a sequence of two VEGFR-TKIs has been used beforehand, the choice is represented by the mTOR inhibitor everolimus, whilst if a VEGFR-TKI followed by everolimus has been chosen, a return to VEGF pathway inhibition is suggested.