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

ABSTRACT

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.

KEYWORDS:

• Renal cell carcinoma
• targeted agents
• second-line therapy
• third-line therapy

Article highlights

• A growing number of mRCC patients are going to receive second, third and further treatment lines.

• Presently, treatment guidelines for second line suggest either to maintain the inhibition of the VEGF/VEGFR pathway or to shift to the inhibition of mTOR.

• In third line, if two VEGFR-TKIs have been previously used, the indication is to move to the mTOR inhibitor everolimus, while, if everolimus has been used second line, going back to the inhibition of the VEGF/VEGFR pathways seems a reasonable choice.

• To date, treatment choice in a second or third line is still largely empirical, based on few randomized controlled trials and other studies, prospective and retrospective, often highly biased.

• The above scenario is going to change radically soon, given the positive results of two large, randomized, controlled, phase III trials of cabozantinib and nivolumab.

This box summarizes key points contained in the article.

Declaration of interest

C Porta acted as a Consultant and/or Speaker for Pfizer, Novartis, GlaxoSmithKline, Bristol-Meyers Squibb, Roche, Exelixis, Bayer-Schering, Astellas and Pierre Fabre. C Paglino acted as a Consultant and/or Speaker for Pfizer, Novartis and GlaxoSmithKline; presently, she is an Employee of Novartis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.