Therapeutic Strategies for Patients With Metastatic Renal Cell Carcinoma in Whom First-Line Vascular Endothelial Growth Factor Receptor-Directed Therapies Fail

Metastases are present in one third of renal cell carcinomas at diagnosis. The overall survival duration in metastatic renal cell carcinoma is approximately 22 months, which underlines the need for more effective systemic treatments. Therapies on the basis of antiangiogenic agents and inhibitors of the mammalian target of rapamycin have been approved for treatment of metastatic renal cell carcinoma, but only benefits for progression-free survival were demonstrated in the second-line setting. Fortunately, promising treatments are emerging, from new antiangiogenic agents to immune checkpoint inhibitors. For the first time, both an immune checkpoint inhibitor (nivolumab) and a dual inhibitor of the tyrosine kinases c-Met and vascular endothelial growth factor receptor-2 (cabozantinib) have demonstrated improvements in overall survival in the second-line setting. Finding the best sequence for these novel agents will be crucial to improving outcomes in patients with metastatic renal cell carcinoma. This article comprises both a systematic review of the literature and recommendations for second-line therapeutic strategies for patients with metastatic clear cell renal cell carcinoma in whom inhibitors of vascular endothelial growth factor have failed.