Combination bezafibrate and nivolumab treatment of patients with advanced non–small cell lung cancer

Despite the success of cancer immunotherapies such as programmed cell death–1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors, patients often develop resistance. New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this issue. Bezafibrate, a ligand of peroxisome proliferator–activated receptor–γ coactivator 1α/peroxisome proliferator–activated receptor 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 1 trial (UMIN000017854) 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 up-regulation 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. Description Combination bezafibrate and nivolumab was safe and boosted anti-tumor immunity in patients with metastatic NSCLC. Targeting T cell metabolism Targeting T cell metabolismImmune checkpoint inhibition (ICI) has improved survival for patients with non-small cell lung cancer (NSCLC), however, 30-50% of patients are unresponsive or acquire resistance. To improve survival of patients, Tanaka et al. have taken guidance from previous preclinical studies where Bezafibrate has shown synergy with ICIs and have implemented a phase I trial (UMIN000017854) of bezafibrate with nivolumab in previously treated patients with advanced NSCLC. The authors found that the regimen was well tolerated, saw partial response in 12 out of 18 patients, and promoted T cell function. This combination targeting T cell metabolism shows promise at potentiating the effects of ICIs and warrants further study.– DH