Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors.
Phase 1 study of pembrolizumab (MK-3475; anti-PD-1 monoclonal antibody) in Japanese patients with advanced solid tumors.
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DOI：
10.1007/s10637-016-0347-6
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发表时间：
2016-06
影响因子：
3.4
通讯作者：
Nakagawa K
中科院分区：
文献类型：
--
作者：
Shimizu T;Seto T;Hirai F;Takenoyama M;Nosaki K;Tsurutani J;Kaneda H;Iwasa T;Kawakami H;Noguchi K;Shimamoto T;Nakagawa K
本I期研究评价了pembrolizumab在日本晚期实体瘤患者中的安全性和耐受性、药代动力学和药效学、免疫原性和抗肿瘤活性。方法在初始剂量和28天停药（第1周期）后，Pembrolizumab以每2周（Q2 W）递增剂量（2或10 mg/kg）静脉输注，直至疾病进展或不可接受的毒性。使用CTCAE v4.0评估不良事件（AE），使用RECIST v1.1和免疫相关缓解标准（irRC）评估肿瘤缓解。在周期1期间进行完整的药代动力学采样。结果3例患者接受2.0 mg/kg的帕博利珠单抗治疗，7例患者接受10 mg/kg的帕博利珠单抗治疗。在第1周期期间未观察到剂量限制性毒性。80%的患者发生药物相关AE（大多数为1级或2级）;最常见的药物相关AE为恶心、不适、发热和天冬氨酸转氨酶/丙氨酸转氨酶（AST/ALT）升高（各n = 2）。未发生药物相关的4级或5级AE。免疫相关AE包括3级ALT升高（n = 1）、3级AST升高（n = 1）、1级肺炎（n = 1）和1级促甲状腺激素升高（n = 1）。日本患者的安全性和药代动力学特征与既往报告的白人患者相似。在1例非小细胞肺癌（NSCLC）患者和1例黑色素瘤患者中观察到部分肿瘤缓解。结论Pembrolizumab 2和10 mg/kg Q2 W在日本晚期实体瘤患者中耐受性良好，对黑色素瘤和NSCLC显示出令人鼓舞的抗肿瘤活性。
Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.