尼伏魯單抗加伊匹木單抗在以前用索拉非尼治療的晚期肝細

StephenW

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial
Thomas Yau  1 , Yoon-Koo Kang  2 , Tae-You Kim  3 , Anthony B El-Khoueiry  4 , Armando Santoro  5 , Bruno Sangro  6 , Ignacio Melero  7 , Masatoshi Kudo  8 , Ming-Mo Hou  9 , Ana Matilla  10 , Francesco Tovoli  11 , Jennifer J Knox  12 , Aiwu Ruth He  13 , Bassel F El-Rayes  14 , Mirelis Acosta-Rivera  15 , Ho-Yeong Lim  16 , Jaclyn Neely  17 , Yun Shen  18 , Tami Wisniewski  19 , Jeffrey Anderson  19 , Chiun Hsu  20
Affiliations
Affiliations

    1
    Department of Medicine, University of Hong Kong, Hong Kong, China.
    2
    Asan Medical Center, Department of Oncology, University of Ulsan, Seoul, South Korea.
    3
    Department of Internal Medicine, Seoul National University, Seoul, South Korea.
    4
    Norris Comprehensive Cancer Center, Division of Medical Oncology/Hematology, University of Southern California, Los Angeles, California.
    5
    Humanitas Clinical and Research Center, Department of Medical Oncology, Humanitas University, Rozzano, Italy.
    6
    Department of Internal Medicine, Clinica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra, and Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Pamplona, Spain.
    7
    Department of Immunology and Immunotherapy, Clinica Universidad de Navarra and Centro de Investigación Biomédica en Red de Cáncer, Pamplona, Spain.
    8
    Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
    9
    Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.
    10
    Department of Medicine, Servicio de Digestivo, Hospital General Universitario Gregorio Marañón, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Madrid, Spain.
    11
    Department of Medical & Surgical Sciences, University of Bologna, Bologna, Italy.
    12
    Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
    13
    Division of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
    14
    Department of Hematology, Emory University Winship Cancer Institute, Atlanta, Georgia.
    15
    Department of Hematology and Oncology, Fundacion de Investigacion, San Juan, Puerto Rico.
    16
    Samsung Medical Center, Department of Hematology and Oncology, Sungkyunkwan University School of Medicine, Seoul, South Korea.
    17
    Department of Immuno-Oncology, Biomarkers, and Translational Medicine, Bristol Myers Squibb, Princeton, New Jersey.
    18
    Department of Immuno-Oncology, Oncology, and Immunology, Bristol Myers Squibb, Princeton, New Jersey.
    19
    Department of Clinical Research, Bristol Myers Squibb, Princeton, New Jersey.
    20
    Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.

    PMID: 33001135 DOI: 10.1001/jamaoncol.2020.4564

Abstract

Importance: Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy.

Objective: To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib.

Design, setting, and participants: CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C).

Interventions: Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C).

Main outcomes and measures: Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1).

Results: Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis).

Conclusions and relevance: In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study.

Trial registration: ClinicalTrials.gov Identifier: NCT01658878.
Associated data

    ClinicalTrials.gov/NCT01658878

StephenW

尼伏魯單抗加伊匹木單抗在以前用索拉非尼治療的晚期肝細胞癌中的療效和安全性：CheckMate 040隨機臨床試驗
丘馬（Thomas Yau）1，尹允九（Koon-Koo Kang）2，金泰佑（Tae-You Kim）3，安東尼·B·艾爾·庫埃里（Anthony B El-Khoueiry）4，阿曼多·桑托羅（Armando Santoro）5，布魯諾·桑格羅（Bruno Sangro）6，伊格納西奧·梅勒羅（Ignacio Melero）7，工藤正敏（Masatoshi Kudo）8，名模侯9（Hing-Mo Hou）9，安娜·馬蒂拉（Ana Matilla）10，弗朗切斯科（Francesco） Tovoli 11，Jennifer J Knox 12，Aiwu Ruth He 13，Bassel F El-Rayes 14，Mirelis Acosta-Rivera 15，Ho-Yeong Lim 16，Jaclyn Neely 17，Yun Shen 18，Tami Wisniewski 19，Jeffrey Anderson 19，Chiun Hsu 20
隸屬關係
隸屬關係

    1個
    香港大學醫學系，香港，中國。
    2
    蔚山大學腫瘤學系，牙山醫學中心，韓國首爾。
    3
    首爾國立大學內科，韓國首爾。
    4
    南加州大學醫學腫瘤學/血液學系諾里斯綜合癌症中心，加利福尼亞州洛杉磯。
    5
    意大利羅扎諾人道大學醫學腫瘤學係人道臨床研究中心。
    6
    納瓦拉大學醫學院，納瓦拉衛生研究所和內華大學生物醫學研究中心，西班牙潘普洛納。
    7
    納瓦拉大學臨床免疫和免疫治療學系，西班牙潘普洛納的生物醫學研究中心。
    8
    日本大阪大學近代醫學院醫學院消化病學和肝病學系。
    9
    台灣台北市長庚紀念醫院內科血液腫瘤科
    10
    西班牙馬德里中央大學格雷戈里奧里奧·馬拉尼昂大學綜合醫院Servicio de Digestivo醫院醫學部。
    11
    意大利博洛尼亞大學博洛尼亞大學醫學與外科科學系。
    12
    加拿大安大略省瑪格麗特公主癌症中心癌症臨床研究室。
    13
    華盛頓特區喬治敦大學醫學中心，倫巴第綜合癌症中心血液學/腫瘤學科。
    14
    喬治亞州亞特蘭大市埃默里大學Winship癌症研究所血液學系。
    15
    波多黎各聖胡安基金會研究中心血液學和腫瘤學系。
    16
    成均館大學醫學院血液學與腫瘤學系三星醫學中心，韓國首爾。
    17
    新澤西州普林斯頓的布里斯托爾·邁爾斯·斯奎布（Bristol Myers Squibb）免疫腫瘤學，生物標誌物和轉化醫學系。
    18歲
    新澤西州普林斯頓的布里斯托爾·邁爾斯·斯奎布（Bristol Myers Squibb）免疫腫瘤學，腫瘤學和免疫學系。
    19
    新澤西州普林斯頓的布里斯托爾·邁爾斯·斯奎布（Bristol Myers Squibb）臨床研究系。
    20
    國立台灣大學附屬醫院腫瘤科，台灣台北。

    PMID：33001135 DOI：10.1001 / jamaoncol.2020.4564

抽象

重要性：大多數患有肝細胞癌（HCC）的患者被診斷出患有不適合進行潛在治療的晚期疾病；因此，需要新的治療方案。與nivolumab單藥治療相比，將nivolumab與ipilimumab合併可以改善臨床結局。

目的：評估尼伏魯單抗聯合依匹莫單抗在先前接受索拉非尼治療的晚期肝癌中的療效和安全性。

設計，設置和參與者：CheckMate 040是一項多中心，開放標籤，多隊列，1/2期研究。在nivolumab加ipilimumab隊列中，患者在2016年1月4日至9月26日之間隨機分組。隨機分組後，治療組信息不可見。中位隨訪時間為30.7個月。該分析的數據截止日期為2019年1月。患者在亞洲，歐洲和北美的10個國家/地區的31個中心招募。符合條件的患者先前曾用索拉非尼治療過的晚期肝癌（有或沒有乙肝或丙肝）。總共148例患者被隨機分組（A臂50例，B和C臂49例）。

干預措施：將患者按1：1：1的比例隨機分配：每3週一次（4劑）給予nivolumab 1 mg / kg加上ipilimumab 3 mg / kg，然後每2週給予240 mg（根據A組）。每3週（4劑）給予nivolumab 3 mg / kg加ipilimumab 1 mg / kg，然後每2週給予240 mg（nivolumab）治療（B組）；或每2週3 mg / kg的尼古魯單抗加每6週1 mg / kg的ipilimumab（C組）。

主要結果和措施：主要終點是安全性，耐受性和客觀緩解率。還測量了反應的持續時間（研究人員根據《實體瘤反應評估標準》 v1.1進行了評估）。

结论与相关性：在这项随机临床试验中，nivolumab加上ipilimumab具有可控的安全性，有希望的客观反应率和持久的反应性。 根据这项研究的结果，A组方案（每3周给予4剂nivolumab 1 mg / kg加ipilimumab 3 mg / kg，然后每2周给予nivolumab 240 mg）在美国获得加速批准。

试验注册：ClinicalTrials.gov标识符：NCT01658878。
关联数据

     ClinicalTrials.gov/NCT01658878