Second-Line Treatment Landscape for Renal Cell Carcinoma: A Comprehensive Review

The management of advanced clear-cell renal cell carcinoma has steadily improved over the past decade with the introduction of antiangiogenic and targeted therapies. Recently, three new therapies have been approved for use as second-line options that further advance the treatment armamentarium: nivolumab, a monoclonal antibody targeting the programmed cell death receptor; cabozantinib, a small-molecule tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR), MET, and AXL; and lenvatinib, a small-molecule TKI of VEGF and fibroblast growth factor receptors that is used in combination with everolimus, an inhibitor of the mechanistic target of rapamycin. Together, these and previously approved second-line treatments offer clinicians the ability to better individualize treatment for patients after progression on first-line VEGFR-targeted therapies. In this comprehensive review, we discuss the efficacy and safety results from the pivotal trials of these newly approved therapies, including the quality of study design, the level of evidence, subgroup analyses, and how these data can help to guide clinicians to select the most appropriate second-line therapy for their patients.