Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study

Abstract

Background: To assess the safety profile, pharmacokinetics, pharmacodynamics and preliminary antitumour activity of fixed-dose SHR-1210, a novel anti-PD-1 antibody, in advanced solid tumours.

Methods: A total of 36 patients with advanced solid tumours received intravenous SHR-1210 at 60 mg, 200 mg and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The concentration of SHR-1210 was detected for pharmacokinetics, and receptor occupancy on circulating T lymphocytes was assessed for pharmacodynamics.

Results: No dose-limiting toxicities were observed. Maximum administered dose was not reached. Most adverse events were grade 1 or 2. Treatment-related severe adverse events were found in two patients. No treatment-related death was reported. Two complete responses (gastric cancer, bladder carcinoma) and seven partial responses were seen. In responders, the median follow-up time was 16.0 months (range 8.3-19.5), and the median duration of response was not reached (range 2.7-17.5+ months). The half-life of SHR-1210 was 2.94 d, 5.61 d and 11.0 d for 3 dose levels, respectively.

Conclusions: Our results demonstrated a promising antitumour activity and a manageable safety profile of SHR-1210, displayed an explicit PK evidence of the feasibility of fixed dose, and established the foundation for further exploration.

Fig. 1

Antitumour activity of SHR-1210 in patients with advanced solid cancers. a The best change from baseline in the sum of the longest target lesion diameters per patient. b Duration of disease control. c Longitudinal change from baseline in the sum of the longest target lesion diameters. Responses were assessed in accordance with the RECIST v1.1 by independent review in all 36 patients. Colour code defines dose level of treatment with SHR-1210. Green, blue, purple bars represent dose levels 60 mg, 200 mg and 400 mg, respectively. The golden pentastar indicates patients with partial response. The red circle indicates patients with progressive disease at the first evaluation. The red triangle indicates patients with progressive disease after non-progressive disease. The black star represents the last dose of SHR-1210 patients receive. The black arrow indicates those patients who are still under treatment at the time of data collection

Fig. 2

Mean serum concentration-time profiles of SHR-1210 and PD-1 receptor occupancy rates after a single infusion at 60 mg (a), 200 mg (b) and 400 mg (c)