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.
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。
Keywords: Atezolizumab; China; Neoplasms; Pharmacokinetics.