title: Targeted therapy for renal cell carcinoma: focus on 2nd and 3rd line.
abstract: BACKGROUND
  Second- and third-line treatments are more and more frequently administered to metastatic renal cell carcinoma (mRCC) patients.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Medical Oncology , I.R.C.C.S. San Matteo University Hospital Foundation , Pavia , Italy.|b Italian Group of Nephro-Oncology/Gruppo Italiano di Oncologia Nefrologica (G.I.O.N.).
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.affiliation: a Medical Oncology , I.R.C.C.S. San Matteo University Hospital Foundation , Pavia , Italy.
authors.forename: Palma
authors.initials: P
authors.lastname: Giglione
authors.affiliation: a Medical Oncology , I.R.C.C.S. San Matteo University Hospital Foundation , Pavia , Italy.|b Italian Group of Nephro-Oncology/Gruppo Italiano di Oncologia Nefrologica (G.I.O.N.).
authors.forename: Chiara
authors.initials: C
authors.lastname: Paglino
mesh_terms: D000813:Anilides / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D000068338:Everolimus / Q000627:therapeutic use; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D000077594:Nivolumab; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000813:Anilides; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; D000077594:Nivolumab; D000068338:Everolimus; D040262:Receptors, Vascular Endothelial Growth Factor; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Renal cell carcinoma; second-line therapy; targeted agents; third-line therapy