Yoichi Nakanishi

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.

Background: As docetaxel plus S-1 may be feasible for cancer treatment, we conducted a phase I/II trial to determine the recommended docetaxel dose and the fixed S-1 dose (phase I), as well as confirm the regimen’s efficacy and safety (phase II) for previously-treated patients with advanced non-small cell lung cancer. Methods: Patients ≤75 years with performance status ≤1 and adequate organ function were treated at three-week intervals with docetaxel on day 1 and 80 mg/m² oral S-1 from days 1–14. The starting docetaxel dose was 45 mg/m² and this was escalated to a maximum of 70 mg/m². In phase II, response rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. Results: The recommended doses were 50 mg/m² docetaxel (day 1) and 80 mg/m² S-1 (days 1–14). Grades 3 and 4 leukocytopenia and neutropenia occurred in 44% and 67% of patients, respectively. Nonhematologic toxicities were generally mild. Overall response to chemotherapy was 7.7% (95% confidence interval (CI), 1.6–20.9%), and median PFS and OS were 18.0 weeks (95% CI; 11.3–22.9 weeks) and 53.0 weeks, respectively. Conclusion: Fifty mg/m² docetaxel plus 80 mg/m² oral S-1 had a lower response rate than anticipated; however, the survival data were encouraging. A further investigation is warranted to select the optimal patient population.