Sequential therapy in metastatic clear cell renal carcinoma: TKI–TKI vs TKI–mTOR

Abstract

With seven targeted agents, directed against the VEGF/VEGF receptor (VEGFR) axis or the mTOR pathway, approved for the treatment of metastatic renal cell carcinoma and more active agents in advanced phase of clinical testing, questions have arisen with regard to their optimal use, either in combination or in sequence. One of the most compelling (and debated) issues is whether continued VEGF/VEGFR inhibition with agents hitting the same targets (TKI–TKI) affords better results than switching mechanisms of action by alternating VEGFR and mTOR inhibition (TKI–mTOR). In this article, the authors review the (little) available evidence coming from randomized Phase III clinical trials and try to fill in the (many) remaining gaps using evidence from small-size, single-arm Phase II studies and retrospective series, as well as reviewing preclinical evidence supporting either strategy.

Keywords::

• metastatic
• mTOR inhibitors
• renal cell carcinoma
• second-line treatment
• sequential therapy
• VEGF receptor-tyrosine kinase inhibitor

Financial & competing interests disclosure

This work was supported in part by grants from the Italian Association for Cancer Research (AIRC 5 x mille Special Program on Clinical and Molecular Oncology and IG 11930), the Italian Ministry of Health and the Italian Ministry of University and Research (MIUR-PRIN 2009X23L78_005). The authors have no relevant affiliations or financial involvement with any other organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.