Clinical activity of immunotherapy-based combination first-line therapies for metastatic renal cell carcinoma: the right treatment for the right patient

Immunotherapy (IO) with checkpoint inhibitors with or without anti-angiogenic tyrosine kinase inhibitor (TKI)-based combinations have demonstrated superior efficacy over sunitinib for treatment-naive patients with metastatic clear-cell renal cell carcinoma (mRCC). Four of these combinations (nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib and pembrolizumab plus lenvatinib) represent new front-line standard-of-care options for mRCC patients, according to the International Metastatic RCC Database Consortium (IMDC) subgroups. Questions over the optimal treatment between IO–IO or IO–TKI combinations for mRCC patients in intermediate/poor IMDC risk groups and the optimal IO–TKI regimen for all IMDC risk groups remain unanswered. This review will focus on the biological pathways that have driven the hypothesis of a synergistic combination of such agents and their efficacy results, with consideration of response and survival outcomes in the overall population of phase three pivotal trials as well as in specific subgroups of interest.