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.