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Simple Summary  First-line treatment options for metastatic clear cell renal cell carcinoma have significantly increased. The current recommended therapeutic strategy is based on a combination, but monotherapy remains an alternative. However, the choice of the type of combination, i.e., dual immunotherapy or immunotherapy combined with an antiangiogenic drug, has not been clearly standardized. A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. This review summarizes all recent data from the main combinations evaluated in first-line treatment and discusses the choice of drugs according to the patient’s profile and the benefit/risk balances of each combination.    Abstract  The development of antiangiogenic treatments, followed by immune checkpoint inhibitors (ICI), has significantly changed the management of metastatic clear cell renal cell cancer. Several phase III trials show the superiority of combination therapy, dual immunotherapy (ICI-ICI) or ICI plus tyrosine kinase inhibitors (TKI) of the vascular endothelium growth factor (VEGF) over sunitinib monotherapy. The question is therefore what is the best combination for a given patient? A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. However, several issues remain unresolved and require further investigation, such as the PD-L1 status, the relevance of possible options based on the patient’s profile, and consideration of second-line and subsequent treatments.

First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma: What Are the Most Appropriate Combination Therapies?