Evolving Frontline Treatment Landscape for Advanced or Metastatic Renal Cell Carcinoma

The treatment landscape of metastatic renal cell carcinoma (mRCC) is evolving very rapidly. Until recently, targeted monotherapy with vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors (TKIs) such as sunitinib, pazopanib and cabozantinib were considered the predominant frontline treatment options. In 2018, combination immune checkpoint inhibitor (ICI) therapy with ipilimumab and nivolumab was approved by the United States' Food and Drug Administration (FDA) for intermediate- and poor-risk patients. Subsequently, the FDA approved combination regimens consisting of a VEGF-TKI with an immune checkpoint inhibitor for all risk categories: pembrolizumab-axitinib and avelumb-axitinib. In the context of these new developments and several ongoing trials in treatment naive clear-cell mRCC, there remains a dilemma among treating physicians about the choice of the most appropriate therapy as well as how to sequence these agents. In this review, we aim to highlight the available data on immunotherapy-based combinations and to provide a contemporary perspective on the optimal approach to patients with mRCC.