Immune Checkpoint Inhibitors: Toward New Paradigms in Renal Cell Carcinoma.

Immune modulatory treatment regimens, led by immune checkpoint inhibitors, have transformed the treatment of clear-cell renal cell carcinoma. First-in-class, the PD-1 inhibitor nivolumab improved overall survival in advanced renal cell carcinoma following prior anti-angiogenic therapy, an important shift in the management of clear-cell renal cell carcinoma. Further improvements of long-term outcomes will be driven by combinations in the first-line setting, including PD-1/PD-L1 associated with antiangiogenic therapies, or PD1/PD-L1 inhibitors with other immune checkpoint inhibitors such as anti-CTLA-4, anti-LAG-3 or TIM-3 targeted therapies. The first two randomized Phase 3 trials assessing these combinations have now challenged sunitinib in first-line setting. First, the CheckMate 214 trial demonstrated an objective response rate and overall survival benefit for the combination of nivolumab plus ipilimumab in the intermediate- and poor-risk patients. Second, the IMMotion 151 study demonstrated a progression-free survival benefit for the atezolizumab plus bevacizumab combination by investigator assessment. Further Phase 3 trials are awaited with tyrosine kinase and immune checkpoint inhibitor combinations. Clinical trials of immune checkpoint inhibitors are also actively investigated in the localized adjuvant or neoadjuvant setting. Nevertheless, the search for biomarkers along with new clinical trial designs will be crucial to better select the patients that may derive the greatest benefit from these advances. The continuing improvement of antitumor immunity comprehension and the emergence of new immune modulatory treatments will deeply change the management of renal cell carcinoma for the years to come.