Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib The CheckMate 040 Randomized Clinical Trial

• Type of Material: Article
• Authors: Thomas Yau, University of Hong Kong; Yoon-Koo Kang, University of Ulsan; Tae-You Kim, Seoul National University; Anthony B. El-Khoueiry, University of Southern California; Armando Santoro, Humanitas University; Bruno Sangro, Clinica Universidad de Navarra; Ignacio Melero, Clinica Universidad de Navarra; Masatoshi Kudo, Kindai University; Ming-Mo Hou, Chang Gung Memorial Hospital; Ana Matilla, Hospital General Universitario Gregorio Marañón; Francesco Tovoli, University of Bologna; Jennifer J. Knox, Princess Margaret Cancer Centre; Aiwu Ruth He, Georgetown University; Bassel El-Rayes, Emory University; Mirelis Acosta-Rivera, Fundacion de Investigacion; Ho-Yeong Lim, Sungkyunkwan University; Jaclyn Neely, Bristol Myers Squibb; Yun Shen, Bristol Myers Squibb; Tami Wisniewski, Bristol Myers Squibb; Jeffrey Anderson, Bristol Myers Squibb; Chiun Hsu, National Taiwan University Hospital
• Language: English
• Date: 2020-11-01
• Publisher: AMER MEDICAL ASSOC
• Publication Version: Final Published Version
• Copyright Statement: 2020 Yau T et al. JAMA Oncology.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1001/jamaoncol.2020.4564
• Title of Journal or Parent Work: JAMA ONCOLOGY
• Volume: 6
• Issue: 11
• Start Page: e204564
• End Page: e204564
• Grant/Funding Information: This study was supported by Bristol Myers Squibb (Princeton, New Jersey) and Ono Pharmaceutical (Osaka, Japan).
• Keywords: Oncology; COMBINATIONS; Life Sciences & Biomedicine; MULTICENTER; OPEN-LABEL; Science & Technology; SURVIVAL; RACE
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology

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.