Phase I Study of Pembrolizumab (MK-3475; Anti–PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors

作者：Amita Patnaik, Soonmo Peter Kang, Drew Rasco, Kyriakos P. Papadopoulos, Jeroen Elassaiss‐Schaap, Muralidhar Beeram, Ronald Drengler, Cong Chen, Lon Smith, Guillermo Espino, Kevin Gergich, Liliana Delgado, Adil Daud, Jill A. Lindia, Xiaoyun Li, Robert H. Pierce, Jennifer H. Yearley, Dianna Wu, Omar Laterza, M. Lehnert, Robert Iannone, Anthony W. Tolcher · 发表于：Clinical Cancer Research · 年份：2015 · DOI：10.1158/1078-0432.ccr-14-2607 · 被引用次数：799 · 研究领域：Cancer Immunotherapy and Biomarkers、CAR-T cell therapy research、Immunotherapy and Immune Responses

PURPOSE: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005-10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratum...