Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma

There has been significant progress in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC), with improved knowledge of disease biology and the introduction of targeted agents and immunotherapies. In this review, we discuss current and emerging first-line treatment options, including recent approvals of the tyrosine kinase inhibitor (TKI) cabozantinib and the immunotherapy combination of nivolumab (anti-programmed cell death 1 [PD-1])/ipilimumab (anti-cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]), and initial outcomes with the combination of atezolizumab (anti-PD-ligand 1 [PD-L1])/bevacizumab (anti vascular endothelial growth factor [VEGF]). Key clinical data are reviewed, as these novel first-line treatments offer significant improvement, particularly for patients classified as intermediate/poor risk for whom previously available therapies have demonstrated limited efficacy. Treatment recommendations based on clinical evidence and expert opinion are discussed. We also review ongoing studies investigating combinations of checkpoint inhibitors with TKIs, including cabozantinib and axitinib, and with other novel immunomodulatory agents, and the potential role of single-agent immunotherapy for select patients. With a growing treatment armamentarium, identification and validation of biomarkers will be crucial for optimizing first-line selection and treatment sequences.