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Abstract Details
Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial
Thomas Yau1, Yoon-Koo Kang2, Tae-You Kim3, Anthony B El-Khoueiry4, Armando Santoro5, Bruno Sangro6, Ignacio Melero7, Masatoshi Kudo8, Ming-Mo Hou9, Ana Matilla10, Francesco Tovoli11, Jennifer J Knox12, Aiwu Ruth He13, Bassel F El-Rayes14, Mirelis Acosta-Rivera15, Ho-Yeong Lim16, Jaclyn Neely17, Yun Shen18, Tami Wisniewski19, Jeffrey Anderson19, Chiun Hsu20
Author information
1Department of Medicine, University of Hong Kong, Hong Kong, China.
2Asan Medical Center, Department of Oncology, University of Ulsan, Seoul, South Korea.
3Department of Internal Medicine, Seoul National University, Seoul, South Korea.
4Norris Comprehensive Cancer Center, Division of Medical Oncology/Hematology, University of Southern California, Los Angeles, California.
5Humanitas Clinical and Research Center, Department of Medical Oncology, Humanitas University, Rozzano, Italy.
6Department 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.
7Department of Immunology and Immunotherapy, Clinica Universidad de Navarra and Centro de Investigación Biomédica en Red de Cáncer, Pamplona, Spain.
8Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
9Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.
10Department of Medicine, Servicio de Digestivo, Hospital General Universitario Gregorio Marañón, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Madrid, Spain.
11Department of Medical & Surgical Sciences, University of Bologna, Bologna, Italy.
12Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
13Division of Hematology/Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
14Department of Hematology, Emory University Winship Cancer Institute, Atlanta, Georgia.
15Department of Hematology and Oncology, Fundacion de Investigacion, San Juan, Puerto Rico.
16Samsung Medical Center, Department of Hematology and Oncology, Sungkyunkwan University School of Medicine, Seoul, South Korea.
17Department of Immuno-Oncology, Biomarkers, and Translational Medicine, Bristol Myers Squibb, Princeton, New Jersey.
18Department of Immuno-Oncology, Oncology, and Immunology, Bristol Myers Squibb, Princeton, New Jersey.
19Department of Clinical Research, Bristol Myers Squibb, Princeton, New Jersey.
20Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
PMID: 33001135
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.