Combination therapy in metastatic renal cell carcinoma: Back to the future?

The treatment landscape of metastatic renal cell carcinoma (mRCC), a chemotherapy-resistant disease, has dramatically changed in the last decade after the introduction of small molecule inhibitors targeting the vascular endothelial growth factor receptor and mammalian target of rapamycin kinases. The CheckMate 025 phase III trial in second line mRCC also introduced immunotherapy with immune-checkpoint inhibitors as an option in the management of mRCC. Both small molecules and immunotherapy are used as single agents and they are associated with different toxicities. Recent data demonstrated that the combination of 2 immunotherapies, nivolumab and ipilimumab, is more effective than tyrosine kinase inhibitors (TKI) monotherapy as first line treatment in intermediate and poor risk mRCC. Furthermore, combination of immunotherapies and TKI has been tested in several trials to evaluate if the combo with agents presenting a different mechanism of action is more effective than monotherapy with TKI. During the past several years, combined therapy of cytokines doublets or cytokines and bevacizumab doublets demonstrated little improvement in clinical outcomes and a relevant toxicity profile. Conversely, the combination of new agents has been recently shown to improve survival in patients with metastatic disease, thus changing the treatment landscape of mRCC. This comprehensive review aims at summarizing the recent advances in the treatment of mRCC.