Abstract
BackgroundTo 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.MethodsA 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.ResultsNo 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.ConclusionsOur 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.
Highlights
Programmed death-1 (PD-1) expressed by activated T lymphocytes is a pivotal immune checkpoint receptor mediating immunosuppression once binding to the Progressive disease (PD)-1 ligands PD-L1 and PD-L2 expressed by tumour cells or stromal cells.[1,2,3] The inhibition of PD-1 and PD-L1 pathway has emerged as one of the most potential therapeutic strategies in a variety of cancers, such as melanoma, lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, etc.[4]
Programmed death-1 (PD-1) expressed by activated T lymphocytes is a pivotal immune checkpoint receptor mediating immunosuppression once binding to the PD-1 ligands PD-L1 and PD-L2 expressed by tumour cells or stromal cells.[1,2,3]
Several monoclonal antibodies against PD-1 and PD-L1 have been developed and under development, such as nivolumab, pembrolizumab, atezolizumab, etc., generating remarkable responses in a wide spectrum of cancers
Summary
Programmed death-1 (PD-1) expressed by activated T lymphocytes is a pivotal immune checkpoint receptor mediating immunosuppression once binding to the PD-1 ligands PD-L1 and PD-L2 expressed by tumour cells or stromal cells.[1,2,3] The inhibition of PD-1 and PD-L1 pathway has emerged as one of the most potential therapeutic strategies in a variety of cancers, such as melanoma, lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, etc.[4]. Monoclonal antibodies are usually given based on the body weight, which has recently been re-evaluated because of the specific properties, and the increased convenience and improved safety of the administration paradigm of fixed dose.[5,6,7] The efficacy of pembrolizumab of 200 mg every 3 weeks (Q3W) has been explored in several phase 3 clinical trials,[8,9,10] with very few pharmacokinetics (PK) evidence of fixed dose. To the best of our knowledge, there are no phase 1 clinical trials evaluating the efficacy of anti-PD-1 antibodies at fixed dose. To assess the safety profile, pharmacokinetics, pharmacodynamics and preliminary antitumour activity of fixeddose SHR-1210, a novel anti-PD-1 antibody, in advanced solid tumours
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