Everolimus - a new approach in the treatment of renal cell carcinoma

Abstract

With the increasing understanding of the biology of the disease and the development of targeted therapy, there has been a paradigm shift in the treatment of clear cell metastatic renal cell carcinoma (mRCC). Traditionally patients with metastatic RCC have been treated with immunotherapy which has limited efficacy. The multikinase inhibitors sunitinib, sorafenib and pazopanib, the VEGF antibody bevacizumab in combination with interferon and the mTOR inhibitor temsirolimus have all been shown to prolong progression-free survival in phase III studies. Here we review another mTOR inhibitor, everolimus (Afinitor(®); Novartis, USA) which was approved in March 2009 by the US FDA for treatment of targeted-therapy refractory metastatic renal cell cancer. The phase III study of everolimus (the RECORD study) was terminated early after a significant difference in efficacy was noted in the treatment arm with everolimus (progression-free survival of 4.0 months in patients on the treatment arm vs 1.9 months in the placebo arm). The most common adverse events were stomatitis, pneumonitis, fatigue and infections. We review Phase I-III data with a particular emphasis on safety data and patient focused outcomes.

Keywords: everolimus; mTOR; metastatic renal cell carcinoma; targeted therapy.

Figure 1

The mTOR pathway. Abbreviations: PI3K, Phophotidyl inositol 3 kinase; PTEN, phosphotase tensin homologue; TSC, tuberous sclerosis complex; mTOR, mamalian target of rapamycin; FKBP-FK506, binding protein; eIF-4E, eukaryotic translation initiation factor; 4E-BP, eukaryotic elongation factor 4E-binding protein; S6K-S, 6 kinase; HIF, hypoxia inducible factor; VEGF, vascular endothelial growth factor.