Potential of Bezafibrate for Combination with Nivolumab in Treatment of Advanced Non-Small Cell Lung Cancer

Background. Novel combination therapies with PD-1/PD-L1 inhibitors are needed to overcome resistance to these drugs. Bezafibrate, a ligand of PGC-1a/PPAR complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase I trial of bezafibrate with nivolumab in previously treated patients with advanced non-small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through upregulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation. 28 samples, PBMC CD8+T cells, before (-1) and after (-2) the treatment of nivolumab and bezafibrate, R: responder, NR: nonresponder