Antiangiogenic Therapy in Clear Cell Renal Carcinoma (CCRC): Pharmacological Basis and Clinical Results

SIMPLE SUMMARY: In the last 15 years, a deep improvement in the knowledge regarding the biological mechanisms responsible for neoplastic cell development and progression has led to a dramatic change in the treatment landscape of metastatic clear cell renal carcinoma. Nowadays, it is known that neo-angiogenesis is a key player in tumor growth and metastatic spread. In particular, the crucial role of the mutation of the von Hippel–Lindau (VHL) tumor suppressor gene, leading to angiogenesis through the transcription of multiple pro-angiogenic factors, is clearly recognized. On the basis of this biological evidence, three classes of targeted therapies with antiangiogenetic activity have received approval for the treatment of advanced disease: tyrosine kinase inhibitors (TKIs); a monoclonal antibody that interferes with vascular endothelial growth factor (VEGF); and two mammalian target of rapamycin (mTOR) inhibitors. These drugs showed impressive results in terms of progression-free survival and objective response rate. In addition, a “second therapeutic revolution” has recently started, due to the latest information on the immunogenic characteristics of renal cell carcinoma and the interplay between angiogenesis and immune surveillance systems. Consequently, immune checkpoint inhibitors, alone or in combination with TKIs, have been approved. In this review, we analyze the pharmacological characteristics and activity of antiangiogenic drugs approved for the treatment of metastatic clear cell renal carcinoma. ABSTRACT: Angiogenesis has a direct stimulatory effect on tumor growth, duplication, invasion and metastatic development. A significant portion of conventional renal cell carcinomas are angiogenesis-dependent tumors and the pathways supporting this process have been thoroughly investigated over the last 20 years. As a consequence, many tyrosine kinase inhibitors (TKIs) (sunitinib, sorafenib, pazopanib, axitinib, and cabozantinib), one monoclonal antibody (bevacizumab), and two mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus) have been investigated and approved for the treatment of advanced or metastatic clear cell renal carcinoma (metastatic CCRC) in first-line, as well as second-line, therapy, with impressive results in progression-free survival and in the objective response rate compared with previously available therapies or placebo. Recently, a new type of drug has been approved for metastatic CCRC: immunomodulatory checkpoint inhibitors (ICIs), alone or in combination with TKIs. However, many questions and areas to be explored still remain with regard to clear cell renal carcinoma (CCRC) treatment: research on predictive biomarkers, the best patient selection, how to overcome the mechanisms of resistance, and the best sequence of therapies in daily clinical practice. This review focuses on the pharmacological properties and anticancer activities of these drugs. The toxicity profile and clinical limitations of these therapies are also discussed.