Phase I Study of Anti-Pd-1 Antibody Ono-4538 and Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer

Aim: ONO-4538 (BMS-936558, nivolumab) is a fully human monoclonal antibody targeting PD-1 (programmed cell death 1) and enhances antitumor activity by blocking PD-1 / PD-L1·L2 (programmed cell death 1 ligand 1·2) binding that down-regulates T-cell co-stimulatory signal. This phase I study investigated the tolerability, safety and pharmacokinetics of ONO-4538 in combination with chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC). Methods: Patients who have stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. ONO-4538 (10 mg/kg, day 1) and chemotherapy [Arm A: cisplatin (80 mg/m2, day 1) / gemcitabine (1250 mg/m2, day 1 and 8), Arm B: cisplatin (75 mg/m2, day 1) / pemetrexed (500 mg/m2, day 1), Arm C: carboplatin (AUC 6, day 1) / paclitaxel (200 mg/m2, day 1) / bevacizumab (15 mg/kg, day 1), Arm D: docetaxel (75 mg/m2, day 1)] were administered every three weeks. Arm A and B were administrated for four cycles and Arm C was for six cycles as first-line chemotherapy. After that, ONO-4538 in Arm A, ONO-4538 / pemetrexed in Arm B, and ONO-4538 / bevacizumab in Arm C were continued every three weeks as maintenance therapy until disease progression. Arm D were administrated until disease progression as second-line chemotherapy. Dose limiting toxicity was evaluated during the first treatment cycle. Results: As of April 10, 2014, six patients each in Arms A to D, total 24 patients [male / female: 17 / 7, PS 0 / 1: 11 / 13), aged 34-73 (median 63) years] were enrolled. Dose limiting toxicity was observed in one patient in Arm A (ALT increased). Severe adverse events were reported in eight patients. Two patients in Arm A, 3 in Arm B, 5 in Arm C, and 1 in Arm D achieved partial response (evaluated by RECIST version 1.1). Conclusions: ONO-4538 10 mg/kg showed acceptable toxicity profile and encouraging antitumor activity in combination with chemotherapy in Japanese patients with advanced NSCLC. Disclosure: T. Tamura: TT has a commercial research grant from Chugai, BMS, Boehringer Ingelheim, Yakult, Abbott, GSK, Eli Lilly, Ono, Kirin, and Quintiles Transnational Japan; and has a honoraria from Taiho, Chigai, and Eli Lilly. All other authors have declared no conflicts of interest.