Combination of Anti-Angiogenics and Checkpoint Inhibitors for Renal Cell Carcinoma: Is the Whole Greater Than the Sum of Its Parts?

SIMPLE SUMMARY: Checkpoint inhibitors and anti-angiogenic therapies are treatments that slow the progression of renal cell carcinoma, the most common type of kidney cancer. Checkpoint inhibitors and anti-angiogenic therapies work in different ways. Checkpoint inhibitors help to prevent tumors from hiding from the body’s immune system, while anti-angiogenic therapies slow the development of blood vessels that tumours need to help them to grow. Studies have shown that treatment with combination checkpoint inhibitor plus anti-angiogenic therapy can achieve better outcomes for patients with renal cell carcinoma than treatment with anti-angiogenic therapy alone. In this review, we consider how combination checkpoint inhibitor plus anti-angiogenic therapy works, and we review the current literature to identify evidence to inform clinicians as to the most effective way to use these different types of drugs, either one after the other, or together, for maximum patient benefit. ABSTRACT: Anti-angiogenic agents, such as vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors and anti-VEGF antibodies, and immune checkpoint inhibitors (CPIs) are standard treatments for advanced renal cell carcinoma (aRCC). In the past, these agents were administered as sequential monotherapies. Recently, combinations of anti-angiogenic agents and CPIs have been approved for the treatment of aRCC, based on evidence that they provide superior efficacy when compared with sunitinib monotherapy. Here we explore the possible mechanisms of action of these combinations, including a review of relevant preclinical data and clinical evidence in patients with aRCC. We also ask whether the benefit is additive or synergistic, and, thus, whether concomitant administration is preferred over sequential monotherapy. Further research is needed to understand how combinations of anti-angiogenic agents with CPIs compare with CPI monotherapy or combination therapy (e.g., nivolumab and ipilimumab), and whether the long-term benefit observed in a subset of patients treated with CPI combinations will also be realised in patients treated with an anti-angiogenic therapy and a CPI. Additional research is also needed to establish whether other elements of the tumour microenvironment also need to be targeted to optimise treatment efficacy, and to identify biomarkers of response to inform personalised treatment using combination therapies.