Front-Line Therapy for Metastatic Renal Cell Carcinoma: A Perspective on the Current Algorithm and Future Directions

Abstract

Over the last decade, the treatment paradigm of metastatic renal cell carcinoma has rapidly evolved, with notable changes in the front-line setting. Combination therapies involving the use of either doublet therapy with immune checkpoint inhibitors or combination VEGFR-directed therapies with immune checkpoint inhibitors have significantly improved clinical outcomes, including prolonged overall survival and durable response to treatment. We aim to highlight the Food and Drug Administration-approved front-line therapy options, the navigation of treatment selection, and the future directions of metastatic renal cell carcinoma therapies.

Keywords: immunotherapy; renal cell carcinoma; targeted therapy.

Figure 1

Mechanism of action of experimental and Food and Drug Administration-approved drugs. In this figure, only the major molecules in each pathway are depicted. Created with BioRender.com. Abbreviations: FGF—fibroblast growth factor; FGFR—FGF receptor; PDGF—platelet-derived growth factor receptor; PDGFR—PDGF receptor; VEGF—vascular endothelial growth factor; VEGFR—VEGF receptor; MET—hepatocyte growth factor receptor; RTK—receptor tyrosine kinase; PI3K—phosphoinositide 3-kinase; AKT—protein kinase B; mTOR—mechanistic target of rapamycin complex; APC—antigen-presenting cell; PD-1—programmed cell death protein; PD-L1—PD-1 ligand 1; PD-L2—PD-1 ligand 2; HIF—hypoxia-inducible factor; HRE—hypoxia response element; pVHL—von Hippel–Lindau protein.