Bevacizumab Plus Immune Checkpoint Inhibition in Renal Cell Carcinoma
Posted: Monday, September 17, 2018
Treatment of metastatic renal cell carcinoma is evolving from single-agent antiangiogenic drugs and immunotherapies to combination regimens designed to optimize antitumor activity. In a review article published in The Cancer Journal, Xin Gao, MD, and David F. McDermott, MD, both of Beth Israel Deaconess Medical Center in Boston, outlined the preclinical rationale for combining antiangiogenic therapies with immune checkpoint inhibitors and highlighted the current status of combinations involving bevacizumab and immune checkpoint inhibitors.
Hyperangiogenesis and high immunogenicity, the targets of available therapies, are major mechanisms of disease development in renal cell carcinoma. Recent preclinical studies revealed that anti-VEGF therapies may also enhance the efficacy of immune checkpoint blockade in addition to antiangiogenesis through a variety of mechanisms mediated by T-cell activation and infiltration, suppression of myeloid-derived suppressor cells, reduction of suppressive cytokines, and induction of memory T cells.
Bevacizumab, which has shown antitumor activity in metastatic disease as monotherapy and in combination with interferon α, is currently being studied in multiple clinical trials involving immune checkpoint inhibitors. The phase III study IMmotion151 found that the combination of bevacizumab plus atezolizumab demonstrated superior progression-free survival over sunitinib in treatment-naive patients with metastatic renal cell carcinoma whose tumor expressed PD-L1. Two phase I/II studies also indicated “encouraging tolerability and clinical efficacy” with histone deacetylase inhibitors in combination with bevacizumab or interleukin-2 in metastatic renal cell carcinoma.
Future studies currently enrolling patients include a phase I/II study of atezolizumab in combination with bevacizumab and the small molecule histone deacetylase inhibitor entinostat, and a single-arm phase Ib/II study of bevacizumab in combination with the PD-1 antibody pembrolizumab in patients with metastatic clear cell renal cell carcinoma.