Programmed cell death-1 (PD-1) is a co-inhibitory receptor expressed on antigen-activated T cell. PD-L1, ligand of PD-1, expressed on various human tumor cells inhibits T-cell activation and proliferation by binding to PD-1. Expression of PD-L1 correlates with poor outcome in renal cell carcinoma, melanoma, non-small-cell lung cancer (NSCLC), and colorectal cancer (CRC). ONO-4538 (BMS-936558) is a fully human monoclonal IgG4 antibody binding to PD-1, and enhances antitumor activity by blocking the PD-1/PD-L1-induced down-regulation of the T-cell co-stimulatory signal. This phase I study investigated the tolerability, pharmacokinetics (PK), antitumor activity and immune response in Japanese patients with advanced solid tumors.Method
Patients with advanced solid tumors refractory to standard therapy, adequate organ functions and performance status of 0 or 1 were enrolled. ONO-4538 was administered intravenously on days 1, 22 and 36 in the first 7 weeks, and then repeated every 2 weeks.Result
Seventeen patients (male/female: 10/7, PS 0/1: 4/13, NSCLC: 5, melanoma: 4, CRC: 4, thymic cancer: 2, esophageal cancer: 1, thyroid cancer: 1, aged 34–74 (median: 61) years) were enrolled at a dose of 1 (n = 3), 3 (n = 5), 10 (n = 6) and 20 (n = 3) mg/kg. The main adverse reactions included lymphopenia (59%), eosinophilia (47%), pyrexia (29%), hypoalbuminemia (29%) and ventricular extrasystole (24%). Grade 3 lymphopenia was observed in two patients, which was resolved without any treatment. No dose-limiting toxic effects were observed up to the dose of 20 mg/kg. The serum concentration of ONO-4538 declined slowly with a terminal half-life of 13–21 days, and the AUC increased proportionally within the dose range investigated. Two out of 17 patients had human anti-human antibodies to ONO-4538 during treatment; however, no remarkable clinical findings were observed. Partial responses were achieved in three patients (CRC at 1 mg/kg, melanoma at 3 mg/kg and thyroid cancer at 10 mg/kg), and the latter two patients continued the treatment >1 years. Three patients (NSCLC at 3 mg/kg, thymic cancer and NSCLC at 10 mg/kg) had stable disease, and the former two patients continued the treatment >6 months.Conclusion
ONO-4538 was well tolerated up to the 20 mg/kg and antitumor activity was observed in several types of advanced solid tumors.