Combinations of Anti-Angiogenic Agents and Immune Checkpoint Inhibitors in Renal Cell Carcinoma: Best Option?

SIMPLE SUMMARY: To summarise the data on the combination of antiangiogenic and immune checkpoints in the treatment of clear-cell renal-cell carcinoma. In this review, we detail the physiopathological rationale of combining tyrosine kinase inhibitors and immunotherapy, and the in vitro and in vivo experiences that first suggested a synergistic effect between these two therapeutic targets. These pre-clinical data led to successful clinical trial that are reviewed in this article. Beyond the main outcomes of the pivotal trials, we describe the features of the different combinations (pembrolizumab-axitinib, pembrolizumab-lenvatinib and cabozantinib-nivolumab) that can help the clinicians to choose between them in routine practice. Eventually we discuss how this new paradigm of combinations will shape the future therapeutic strategies in the treatment of clear-cell renal-cell carcinoma. ABSTRACT: Over the past decade, major advances have been made in the treatment of advanced and metastatic renal cell carcinomas, specifically clear cell carcinomas. For many years the optimal approach was sequential; thus, monotherapies [principally tyrosine kinase inhibitors (TKIs)] targeting angiogenesis until toxicity or progressive disease developed. The rationale was the common mechanisms of action of the targeting agents and avoidance of the risk of overlapping toxicities. Immune checkpoint inhibitors (ICIs) are effective monotherapies, and combinations thereof with anti-angiogenic agents were thus later considered. Synergistic interactions were reported in vitro. Clinical efficacy was evident in three pivotal phase III trials with axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab combinations. Two other combinations showed interesting results but did not improve overall survival. However, the data aided our understanding of the new therapeutic approaches. A combination of the ICIs nivolumab and ipilimumab was the first to evidence better progression-free and overall survival compared to sunitinib in patients with intermediate or unfavourable prognoses as evaluated by the International mRCC Database Consortium (IMDC). Here we focus on the TKI-ICI combinations, emphasising the rationale of their use and the clinical results. To date, no biomarker facilitating the selection of an optimal treatment by disease and patient status has been reported.