阿替利珠单抗治疗中国晚期实体瘤患者的开放标签Ⅰ期临床试验  

Atezolizumab therapy in Chinese patients with locally advanced or metastatic solid tumors:An open-label,phaseⅠstudy

作　　者：张力[1] 龚继芳[2] 潘宏铭[3] 白玉贤[4] 刘天舒 程颖[6] 陈亚池 黄佳莹 许婷婷 葛飞娇 许婉玲 施佳 胡夕春 沈琳[2] ZHANG Li;GONG Ji-fang;PAN Hong-ming;BAI Yu-xian;LIU Tian-shu;CHENG Ying;CHEN Ya-chi;HUANG Jia-ying;XU Ting-ting;GE Fei-jiao;HSU Wan-ling;SHI Jane;HU Xi-chun;SHEN Lin(Department of Medical Oncology,Sun Yat-sen University Cancer Center,Guangzhou 510060,China;Key Laboratory of Carcinogenesis and Translational Research,Ministry of Education,Department of Gastrointestinal Oncology,Peking University Cancer Hospital&Institute,Beijing 100142,China;Department of Medical Oncology,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou 310020,China;Department of Medical Oncology,Harbin Medical University Cancer Hospital,Harbin 150081,China;Department of Medical Oncology,Zhongshan Hospital,Fudan University,Shanghai 200032,China;Department of Medical Oncology,Jilin Cancer Hospital,Changchun 130012,China;Clinical Pharmacology,Genentech,Inc.,South San Francisco,CA 94080,USA;Oncology,Roche Product Development Shanghai,Shanghai,201203,China;Department of Statistics,Roche Product Development Shanghai,Shanghai 201203,China;Portfolio Clinical Safety,Roche Product Development Shanghai,Shanghai 201203,China;Department of Medical Oncology,Fudan University Shanghai Cancer Center,Shanghai 200032,China)

机构地区：[1]中山大学附属肿瘤医院肿瘤内科,广州510060 [2]北京大学肿瘤医院暨北京市肿瘤防治研究所消化肿瘤内科,恶性肿瘤发病机制及转化研究教育部重点实验室,北京100142 [3]浙江大学医学院附属邵逸夫医院肿瘤内科,杭州310020 [4]哈尔滨医科大学附属肿瘤医院肿瘤内科,哈尔滨150081 [5]复旦大学附属中山医院肿瘤内科,上海200032 [6]吉林省肿瘤医院肿瘤内科,长春130012 [7]Clinical Pharmacology,Genentech,Inc.,South San Francisco,CA 94080,USA [8]罗氏全球药品开发中国中心临床科学部,上海201203 [9]罗氏全球药品开发中国中心统计部,上海201203 [10]罗氏全球药品开发中国中心安全部,上海201203 [11]复旦大学附属肿瘤医院肿瘤内科,上海200032

出　　处：《北京大学学报（医学版）》2022年第5期971-980,共10页Journal of Peking University:Health Sciences

摘　　要：目的:观察程序性细胞死亡配体1(programmed death-ligand 1,PD-L1)抑制剂阿替利珠单抗在中国高发实体瘤,包括食管癌(esophageal cancer,EC)、胃癌(gastric cancer,GC)、肝细胞癌(hepatocellular carcinoma,HCC)、鼻咽癌(nasopharyngeal cancer,NPC)和非小细胞肺癌(non-small cell lung cancer,NSCLC)患者中的药代动力学(pharmacokinetics,PK)、疗效和安全性数据。方法:本研究为开放标签的Ⅰ期临床试验,于2016年8月4日至2019年4月15日在中国6个研究中心进行。入组患者年龄≥18岁,患有经组织学证实的无法治愈或转移性的实体瘤,且既往抗肿瘤治疗失败。PK阶段研究了阿替利珠单抗单药治疗的PK和安全性;扩展阶段研究了阿替利珠单抗单药治疗(入组EC、GC、HCC、NPC患者)和联合化疗(入组NSCLC患者)的安全性和有效性。结果:共入组120例患者(PK阶段20例;扩展期每队列20例)。阿替利珠单抗单药组患者(n=100)中有42例(42.0%)为PD-L1阳性,9例(9.0%)为微卫星高度不稳定性。阿替利珠单抗的清除率为0.219 L/d,重复给药6~9周(2~3个周期)后达到稳态。EC、GC、HCC、NPC和NSCLC的客观缓解率(objective response rate,ORR)分别为10.0%、15.0%、10.0%、5.0%和40.0%。在PD-L1阳性的肿瘤患者中,阿替利珠单抗的ORR为11.9%,阿替利珠单抗联合吉西他滨和顺铂的ORR为46.2%。2例GC患者在假性进展后获得了持久的肿瘤缩小。阿替利珠单抗单药组最常见的治疗相关不良事件是疲劳、贫血、发热和白细胞计数减少,联合组最常见的治疗相关AE是贫血、白细胞计数减少和食欲下降。本试验没有发现新的安全信号。结论:中国患者应用阿替利珠单抗的PK、疗效和安全性与之前研究中入组的全球患者的数据相似。Objective:To evaluate pharmacokinetics(PK),efficacy,and safety of atezolizumab(anti-PD-L1)in high interest cancers in China,including esophageal cancer(EC),gastric cancer(GC),hepatocellular carcinoma(HCC),nasopharyngeal cancer(NPC),and non-small cell lung can-cer(NSCLC).Methods:This phase I,open-label study was conducted at 6 Chinese sites from August 4,2016 to April 15,2019.The patients were≥18 years old with a histologically documented incurable or metastatic solid tumor that was advanced or recurrent and had progressed since the last anti-tumor the-rapy.The PK phase characterized PK and safety of atezolizumab following multiple-dose administration when atezolizumab was administered as a single agent.The extension phase studied safety and efficacy of atezolizumab,as monotherapy(EC,GC,HCC,NPC)and with chemotherapy(NSCLC).Results:This study enrolled 120 patients(PK phase:n=20;extension phase:n=20/cohort).Fourty-two patients(42.0%)were PD-L1 positive in atezolizumab monotherapy group(100 patients),of the 9 patients(9.0%)with microsatellite instability-high(MSI-H)tumors.Atezolizumab clearance was 0.219 L/d,and steady state was reached after 6 to 9 weeks(2-3 cycles)of repeated dosing.Objective response rates(ORRs)in EC,GC,HCC,NPC,and NSCLC were 10.0%,15.0%,10.0%,5.0%,and 40.0%,respectively.In the patients with PD-L1 positive tumors,ORR was 11.9%with atezolizumab and 46.2%with atezolizumab plus gemcitabine and cisplatin.Two GC patients achieved durable response after pseudo-progression.The most common treatment-related adverse events in the atezolizumab monotherapy group were fatigue,anemia,fever,and decreased white blood cell count.The most common treatment-related adverse events in the combination group were anemia,decreased white blood cell count,and decreased appetite.No new safety signals were identified.Conclusion:Atezolizumab’s PK,efficacy,and safety were similar in Chinese patients vs.global patients in previous studies.

关 键 词：阿替利珠单抗 药代动力学 中国 肿瘤 

分 类 号：R730.51[医药卫生—肿瘤]