Nivolumab in renal cancer

Abstract

Renal cell carcinoma (RCC) is a chemoresistant tumor, characterized by a poor response and lack of survival benefit with conventional cytotoxic agents. Furthermore, the complexity and heterogeneity of RCC limit the biologic targets for novel agents to manage RCC. Expression of the multiple drug resistance (MDR) protein (ATP-binding cassette P-glycoprotein) is increased in RCC, while the Von Hippel Lindau protein is mutated or silenced in approximately half of sporadic RCC, resulting in high levels of hypoxia inhibiting factor (HIF) and the activation of several genes codifying growth factors and growth factors receptors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor B (PDGF-B), and transforming growth factor alpha (TGFα). Consequently, immunodrugs targeting pathways related to these proteins have been evaluated for the management of metastatic RCC (mRCC). This review provides an overview of drugs that have been evaluated or are under investigation for the treatment of mRCC, including the multi-tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib, axitinib, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and nivolumab, which targets the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway. Promising results have been obtained with nivolumab, alone or in combination with TKIs such as sunitinib and pazopanib, and with ipilimumab, an immune checkpoint inhibitor which acts on the CTLA-4 pathway. Although much progress has been made, research with these and other agents is ongoing, and there is a need to identify makers of response to “tailor” the most suitable therapy, or sequence of therapies, to the individual patient, with the aim of improving outcomes and reducing unneeded toxicity.