Check Point Inhibitors a New Era in Renal Cell Carcinoma Treatment

In the United States, the estimated number of new cases of renal cell carcinoma (RCC) is approximately 65,000 case with about 15,000 deaths in the year of 2018 (Siegel et al. in CA Cancer J Clin 68(1):7, 2018). RCC as an immunogenic malignancy is supported by many theories and facts which include tumor richness of lymphocytes infiltrate, the occurrence of spontaneous tumor regression, and the proved effect of traditional immunotherapy (Finke et al. in J Immunother 11(1):1-11, 1992), all these factors support the potential therapeutic effect of the novel immunotherapeutic agents in RCC. Historically, complete tumor regression in metastatic RCC is achievable in a minority of patients through traditional immunotherapies such as high-dose interleukin-2 (IL-2) (Fyfe et al. in J Clin Oncol 13(3):688, 1995) and interferon-alfa (IFNa) (Negrier et al. in N Engl J Med 338(18):1272, 1998); however due to the significant rate of toxicities and low efficacy; accordingly the targeted therapy with tyrosine kinase inhibitors (TKIs) and vascular endothelial growth factor-antibodies (VEGF) became the standard and prevalent treatment approach for advanced RCC both in front and subsequent lines of therapy (Escudier et al. in Ann Oncol. 25(Suppl 3):iii49-iii56, 2014). A new avenue of immunotherapy utilizing novel strategy to block immune checkpoints has emerged in a new era for RCC treatment (Ascierto et al. in J Transl Med 12:291, 2014). Results from clinical trials are encouraging in both front-line and second-line settings, in a phase III trial (CheckMate 025) nivolumab compared to everolimus improved overall survival in previously treated metastatic RCC who had progressed on prior treatment with targeting agents (Motzer et al. in N Engl J Med 373:1803, 2015). CheckMate 214, a phase III trial, demonstrated superior overall survival and objective response with combined checkpoint inhibitors compared to sunitinib in Treatment-Naïve Advanced RCC among intermediate- and poor-risk group (Motzer et al. in N Engl J Med. 378(14):1277-1290, 2018). In this review, we discuss the systemic Immunotherapy with checkpoint inhibitors that have been approved or are currently being investigated in RCC, clinical experience with these agents, and its future development.