Systemic Treatment of Metastatic Clear Cell Renal Cell Carcinoma in 2018: Current Paradigms, Use of Immunotherapy, and Future Directions

Context: Systemic therapy for metastatic clear cell renal cell carcinoma (mccRCC) has greatly evolved over the last 15yr. More recently, combination strategies involving contemporary immunotherapy have emerged as key opportunities to further shift the treatment landscape.

Objective: To review the evidence regarding the efficacy and safety of standard therapeutic options in mccRCC as well as combination immunotherapy options on the horizon.

Evidence acquisition: PubMed/Medline, Embase, Web of Knowledge, and Cochrane Library databases were searched up to February 2018 and according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. A narrative review of studies was performed.

Evidence synthesis: Twenty-six studies were included regarding therapies for metastatic RCC including vascular endothelial growth factor (VEGF)-directed therapy (n=9), mTOR inhibitors (n=2), cytokines (n=3), vaccines (n=3), and immune checkpoint inhibitors (ICIs, n=9). VEGF tyrosine kinase inhibitor monotherapy had been the standard therapy, and its use is evolving in the front-line setting with ICIs; cabozantinib provides superior progression-free survival versus sunitinib in intermediate- and poor-risk patients, by International Metastatic RCC Database Consortium criteria. The mTOR therapy is largely inferior to VEGF-directed therapy, although it has a role in combination strategies. Cytokines have largely been replaced in current practice throughout most regions, and vaccines have failed to show improved survival in phase III studies to date. ICIs have now become standard care in untreated patients with intermediate and poor risks, given overall survival benefit seen with CheckMate-214 study; survival data from IMmotion 151 are not yet mature. Several ongoing phase III combination trials, with promising early-phase data, are due to be read out.

Conclusions: The treatment landscape for mccRCC has evolved since the introduction of VEGF inhibitors. Combination therapies involving checkpoint inhibitors could be the next standard of care.

Patient summary: With the expanding role of immune checkpoint inhibitors in metastatic renal cell carcinoma, the treatment paradigm has shifted to include combination therapy in the untreated setting. As the field advances, the bar has been raised in evaluating ongoing combination strategies.