《柳叶刀》2017年4月20日在线先发
http://thelancet.com/journals/lancet/article/PIIS0140-6736(17)31046-2/fulltext
纳武单抗（Nivolumab）治疗晚期肝细胞癌（CheckMate 040试验）：一项开放标签、非比较性1/2期剂量递增及扩展试验
背景
对于晚期肝细胞癌患者，索拉非尼是全球仅有的获批药物，但患者预后仍差。为此，我们旨在对晚期肝细胞癌患者不论有无慢性病毒性肝炎，评价纳武单抗（nivolumab）的有效性和安全性，纳武单抗是一种细胞死亡蛋白1（PD-1）免疫检查点抑制剂。
方法
我们在组织学证实为晚期肝细胞癌的成年人（≥18岁）中，不论有无乙型、丙型肝炎，进行了纳武单抗的一项1/2期开放标签、非比较性、剂量递增及扩展试验（CheckMate 040试验），允许既往进行过索拉非尼治疗。在4个国家和地区（美国、西班牙、香港和新加坡）的7家医院或医学研究中心进行了一项剂量递增期研究，在11个国家（加拿大、英国、德国、意大利、日本、韩国、中国台湾）的另外39家医疗机构进行了一项剂量扩展期研究。在筛选患者时，符合入组条件的患者为：对于剂量递增期研究，Child Pugh评分≤7（Child Pugh评分为A或B7）；对于剂量扩展期研究，Child Pugh评分≤6（Child Pugh评分为A），ECOG体能评分≤1。有乙肝病毒感染的患者还必须接受有效的抗病毒治疗（病毒负荷<100 IU/mL），对于丙肝病毒感染的患者不要求抗病毒治疗。我们排除了既往用靶向T细胞共刺激或检查点通路的药物治疗过的患者。在剂量递增期研究中（3+3设计），患者每2周静脉接受一次0.1–10mg/kg纳武单抗治疗；在剂量扩展期研究中，在4个患者队列中给予每2周一次3mg/kg纳武单抗治疗，这4个患者队列为没有病毒性肝炎且索拉非尼未治疗过或不耐受队列、没有病毒性肝炎索拉非尼治疗后进展队列、丙肝感染者队列以及乙肝感染者队列。剂量递增期研究的主要终点为安全性和耐受性，剂量扩展期研究的主要终点为客观缓解率（“实体瘤疗效评价标准1.1”）。本研究已在ClinicalTrials.gov网站注册，注册号NCT01658878。
结果
2012年11月26日至2016年8月8日，治疗了262名符合条件的患者（剂量递增期48名，剂量扩展期214名）。262名患者中有202名（77%）完成了治疗，随访仍在进行。在剂量递增期间，纳武单抗显现出安全性可控，包括耐受性可接受，在该期研究中，48名患者中有46名（96%）中断了治疗，42名（88%）是由于疾病进展。治疗相关的不良反应发生率与用药剂量不相关，且未达到最大耐受剂量；48名患者中有12名（25%）有3/4级治疗相关的不良反应，3名（6%）有治疗相关的严重不良反应（类天疱疮、肾上腺皮质功能减退、肝功异常）；在剂量递增期，48名患者中有30名（63%）死亡（未确定与纳武单抗治疗相关）。选择纳武单抗3mg/kg作为剂量扩展研究。在剂量扩展期研究中纳武单抗3mg/kg治疗的患者，客观缓解率为20%（95%CI，15-26）；在剂量递增期研究中，客观缓解率为15%（95%CI，6-28）。
解释
在晚期肝细胞癌患者中，观察到纳武单抗的安全性可控、无新发症状。持续的客观缓解显示出纳武单抗治疗晚期肝细胞癌的潜质。
Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial
Background
For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis.
Methods
We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1–10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878.
Findings
Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15–26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6–28) in the dose-escalation phase.
Interpretation
Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma.
Funding
Bristol-Myers Squibb.
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