Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
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DOI：
10.1016/s0140-6736(17)31046-2
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发表时间：
2017-06-24
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通讯作者：
Melero I
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作者：
El-Khoueiry AB;Sangro B;Yau T;Crocenzi TS;Kudo M;Hsu C;Kim TY;Choo SP;Trojan J;Welling TH Rd;Meyer T;Kang YK;Yeo W;Chopra A;Anderson J;Dela Cruz C;Lang L;Neely J;Tang H;Dastani HB;Melero I
对于晚期肝细胞癌患者，索拉非尼是全球唯一批准的药物，结果仍然很差。我们的目的是评估nivolumab（一种程序性细胞死亡蛋白-1（PD-1）免疫检查点抑制剂）在伴或不伴慢性病毒性肝炎的晚期肝细胞癌患者中的安全性和有效性。我们在组织学证实的晚期肝细胞癌伴或不伴丙型肝炎或B（HCV或HBV）感染的成人（≥18岁）中进行了一项nivolumab的I/II期、开放标签、非比较、剂量递增和扩展试验（CheckMate 040）。允许既往接受索拉非尼治疗。在四个国家或地区（美国、西班牙、香港和新加坡）的7家医院或学术中心进行了剂量递增阶段，并在11个国家/地区（加拿大、英国、英国）的另外39个研究中心进行了剂量扩展阶段。德国、意大利、日本、韩国、台湾）。筛选时，合格患者的Child-Pugh评分为7分或更低（Child-Pugh A或B7）（剂量递增期）和≤ 6（Child-Pugh A），东部肿瘤协作组体能状态为1或更低。HBV感染患者必须接受有效的抗病毒治疗（病毒载量<100 IU/mL）; HCV感染患者不需要抗病毒治疗。我们排除了既往接受靶向T细胞共刺激或检查点通路药物治疗的患者。患者在剂量递增阶段接受静脉内纳武单抗0·1-10 mg/kg，每2周一次（3+3设计）。纳武单抗3 mg/kg在剂量扩展阶段每2周一次给予4个队列的患者：索拉非尼未治疗或不耐受，无病毒性肝炎，索拉非尼进展者，无病毒性肝炎，HCV感染和HBV感染。主要终点为递增期的安全性和耐受性以及扩展期的客观缓解率（实体瘤缓解评价标准第1.1版）。本研究注册于ClinicalTrials.gov，编号NCT 01658878。2012年11月26日至2016年8月8日期间，262例合格患者接受了治疗（48例患者处于剂量递增阶段，214例患者处于剂量扩展阶段）。262例患者中的202例（77%）已完成治疗，随访正在进行中。在剂量递增期间，nivolumab显示出可管理的安全性特征，包括可接受的耐受性。在该阶段，48例患者中有46例（96%）停止治疗，42例（88%）由于疾病进展。治疗相关不良事件的发生率似乎与剂量无关，并且未达到最大耐受剂量。48例患者中有12例（25%）发生了3/4级治疗相关不良事件。3例（6%）患者发生治疗相关严重不良事件（类天疱疮、肾上腺功能不全、肝脏疾病）。在剂量递增阶段，48例患者中有30例（63%）死亡（未确定与nivolumab治疗相关）。选择Nivolumab 3 mg/kg进行剂量扩展。在剂量扩展阶段接受nivolumab 3 mg/kg治疗的患者中，客观缓解率为20%（95% CI 15-26），在剂量递增阶段为15%（95% CI 6-28）。Nivolumab具有可管理的安全性特征，在晚期肝细胞癌患者中未观察到新信号。持久的客观缓解显示了纳武利尤单抗治疗晚期肝细胞癌的潜力。百时美施贵宝
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. 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. 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. 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. Bristol-Myers Squibb.