Evolving Treatment Paradigm in Metastatic Renal Cell Carcinoma

Abstract

The treatment paradigm for advanced and metastatic renal cell carcinoma (mRCC) has evolved rapidly since the arrival of targeted therapies and novel immunotherapies. mRCC was previously treated only with cytokines. However, discoveries of mutations affecting the von Hippel-Lindau tumor suppressor gene (leading to increased expression of VEGF and hypoxia inducible factor/HIF-1) and of deregulations in the phosphatidylinositol-3 kinase/AKT/mTOR pathway (resulting in tumor angiogenesis, cell proliferation, and tumor growth) have led to the development of numerous targeted therapies. The U.S. Food and Drug Administration (FDA) has thus approved a total of nine targeted therapies since 2005, including VEGF tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, sorafenib, and lenvatinib), a monoclonal antibody targeting VEGF (bevacizumab), mTOR inhibitors (temsirolimus and everolimus), and a multityrosine kinase inhibitor (cabozantinib). Furthermore, the development of immune checkpoint inhibitors has again shifted the mRCC therapeutic landscape with the FDA's approval of nivolumab. Herein, we discuss the unprecedented changes in the field of clear cell histology mRCC in both the first-line and salvage settings, and we also discuss future therapies and recommend a treatment paradigm on sequencing of these agents.

FIGURE 1.. Mechanisms of Action of Targeted Therapies in Metastatic Renal Cell Carcinoma

Ligand binding of RTKs leads to many downstream effects. Proangiogenic RTKs (VEGFR, PDGFR, and FGFR) are labeled in blue, whereas growth factor ligand binding to RTKs is colored orange. Simplified mechanisms of the MAPK pathway (left) and mTOR pathway (right) are labeled in the tumor cell. Activation of HIF-α occurs in states of hypoxia and through lack of inhibition from a nonfunctional VHL gene. It leads to synthesis of VEGF, PDGF, and FGF. This can lead to MAPK activation in endothelial cells, depicted on the left side of the diagram. Through FKBP is the site of action of mTOR inhibitors everolimus and temsirolimus and is labeled in orange. Bevacizumab is a monoclonal antibody directed against VEGF. TKIs include sorafenib, sunitinib, axitinib, pazopanib, cabozantinib, and Ienvatinib. The aforementioned TKIs inhibit multiple RTKs. RTKs of importance are inhibited by the following TKIs: axitinib (VEGFR, PDGFR, c-KIT), sunitinib (VEGFR, PDGFR, RET, c-KIT), sorafenib (VEGFR, PDGFR, RET, c-KIT, Raf kinases), pazopanib (VEGFR, PDGFR, FGFR, c-KIT, RET), Ienvatinib (VEGFR, PDGFR, FGFR, c-KIT, RET), and cabozantinib (VEGFR, c-MET, AXL, c-KIT, RET). Abbreviations: ERK, extracellular signal-regulated kinase; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; FKBP, FK506-binding protein; GAS6, growth arrest-specific 6; HGF, hepatocyte growth factor; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol-3 kinase; RTK, receptor tyrosine kinase; SCF, stem cell factor; TKI, tyrosine kinase inhibitor; VEGFR, VEGF receptor; VHL, von Hippel–Lindau.

FIGURE 2.. Mechanisms of Action of Immunotherapies for Metastatic Renal Cell Carcinoma

Immune checkpoint inhibitors and AGS-003 are featured. Ipilimumab is a monoclonal antibody directed against CTLA-4 on T cells. Nivolumab and pembrolizumab inhibit PD-1 on both tumor and T cells, whereas avelumab and atezolizumab inhibit its ligand, PD-L1. BMS-986016 is a novel immune agent that targets LAG-3, preventing immune inhibition by preventing LAG-3 binding to its ligand, MHC class II receptor. AGS-003 is a mature dendritic cell that has been coelectroporated with tumor DNA and human CD40 ligand. By processing and then presenting tumor antigen, it binds both the TCR and CD28. A third signal leads to with IL-12 promotes memory T-cell development. Abbreviations: IL, interleukin; MHC, major histocompatibility complex; TCR, T-cell receptor.

FIGURE 3.. Sequencing Paradigm of Metastatic Renal Cell Carcinoma

Asterisks indicate that nivolumab, cabozantinib, and lenvatinib plus everolimus are currently approved for use only after previous antiangiogenic therapy. After failure of HDIL-2, patients could receive axitinib or sorafenib. Abbreviations: HDIL-2, high-dose interleukin-2.