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

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          Key Points

          Question

          Does adding ipilimumab to nivolumab improve clinical outcomes for patients with advanced hepatocellular carcinoma previously treated with sorafenib?

          Findings

          In the CheckMate 040 randomized clinical trial of nivolumab plus ipilimumab in patients with advanced hepatocellular cancer previously treated with sorafenib, patients were randomized 1:1:1 to 3 different treatment arms to evaluate different dosing regimens. Investigator-assessed objective response rate was greater than 30% across treatment arms, and the combination of nivolumab plus ipilimumab led to high overall survival rates and had a manageable safety profile.

          Meaning

          The manageable safety profile and promising response rates observed in this study support further investigation of nivolumab plus ipilimumab as a treatment option for this patient population.

          Abstract

          This randomized clinical trial assesses the efficacy of nivolumab plus ipilimumab in the treatment of patients with advanced hepatocellular carcinoma who have been previously treated with sorafenib.

          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

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          Most cited references28

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          • Article: not found

          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

            Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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              Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial

              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.
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                Author and article information

                Journal
                JAMA Oncol
                JAMA Oncol
                JAMA Oncology
                American Medical Association
                2374-2437
                2374-2445
                November 2020
                1 October 2020
                1 October 2020
                : 6
                : 11
                : e204564
                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
                Author notes
                Article Information
                Accepted for Publication: July 17, 2020.
                Published Online: October 1, 2020. doi:10.1001/jamaoncol.2020.4564
                Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2020 Yau T et al. JAMA Oncology.
                Corresponding Author: Thomas Yau, MD, Department of Medicine, University of Hong Kong, 102 Pok Fu Lam Rd, Hong Kong 999077, China ( tyaucc@ 123456hku.hk ).
                Author Contributions: Dr Yau had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Yau, El-Khoueiry, Sangro, Melero, Lim, Anderson.
                Acquisition, analysis, or interpretation of data: Yau, Kang, Kim, El-Khoueiry, Santoro, Melero, Kudo, Hou, Matilla, Tovoli, Knox, Ruth He, El-Rayes, Acosta-Rivera, Lim, Neely, Shen, Wisniewski, Anderson, Hsu.
                Drafting of the manuscript: Yau, El-Khoueiry, Santoro, Melero, El-Rayes, Lim, Shen, Wisniewski, Anderson, Hsu.
                Critical revision of the manuscript for important intellectual content: Yau, Kang, Kim, El-Khoueiry, Sangro, Melero, Kudo, Hou, Matilla, Tovoli, Knox, Ruth He, El-Rayes, Acosta-Rivera, Lim, Neely, Wisniewski, Anderson, Hsu.
                Statistical analysis: Yau, Lim, Shen, Anderson.
                Administrative, technical, or material support: Yau, Hou, Knox, El-Rayes, Acosta-Rivera, Lim, Neely, Wisniewski, Hsu.
                Supervision: Yau, Kim, El-Khoueiry, Melero, Kudo, Hou, Ruth He, El-Rayes, Lim, Anderson, Hsu.
                Conflict of Interest Disclosures: Dr Yau reported receiving personal fees from Bristol Myers Squibb during the conduct of the study; and grants and personal fees from Bristol Myers Squibb, personal fees from Merck Sharp & Dohme Oncology, Exelixis, Ipsen, and AstraZeneca outside the submitted work. Dr Kang reported personal fees from Bristol Myers Squibb, ALX Oncology, Novartis, and Surface Oncology outside the submitted work. Dr El-Khoueiry reported grants and nonfinancial support from Bristol Myers Squibb during the conduct of the study; personal fees from Bristol Myers Squibb, Bayer, Eisai Co, Merck, Roche/Genentech, Exelixis, AstraZeneca, Agenus, EMD Serono, Zymeworks, Agios, QED Therapeutics, Cytomx, Pieris, and Target PharmaSolutions outside the submitted work. Dr Santoro reported other support from Bristol Myers Squibb, Laboratoires Servier, Gilead Sciences, Pfizer, Eisai Co, Bayer, Merck Sharp & Dohme, ArQule Inc, Sanofi, Takeda, Bristol Myers Squibb, Roche, AbbVie, Amgen, Celgene, Laboratoires Servier, Gilead Sciences, AstraZeneca, Pfizer, Eli Lilly, Sandoz, and Novartis outside the submitted work. Dr Sangro reported personal fees from AstraZeneca, Adaptimmune Limited, Bayer, H3 Biomedicine, Ipsen, Eli Lilly, Roche/Genentech, and BTG; and grants and personal fees from Bristol Myers Squibb and Sirtex Medical outside the submitted work. Dr Melero reported personal fees from Bayer, Servier, Numab, Pieris, and Merck Sharp & Dohme, and grants and personal fees from Bristol Myers Squibb, Roche, Bioncotech, Alligator, AstraZeneca, and Merck Serono during the conduct of the study. Dr Kudo reported grants and other support from Eisai; other support from Bayer, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, and Ono Pharmaceutical; grants from Gilead Sciences, Taiho Pharmaceutical, Sumitomo Dainippon Pharma, Takeda Pharmaceutical Company, Otsuka Pharmaceutical, EA Pharma Co, and AbbVie outside the submitted work. Dr Matilla reported personal fees from Bristol Myers Squibb during the conduct of the study, and personal fees from Bristol Myers Squibb, Bayer, Boston Scientific, Terumo, and Eisai outside the submitted work. Dr Tovoli reported personal fees and nonfinancial support from Bayer AG and personal fees from LaForce outside the submitted work. Dr Knox reported grants from Ipsen and grants and personal fees from AstraZeneca, Merck, and F. Hoffman-La Roche outside the submitted work. Dr El-Rayes reported grants and personal fees from Bristol Myers Squibb during the conduct of the study; grants and personal fees from Merck, grants from Boston Biomedical, Pfizer, Novartis, MedImmune, Xencor, EUSA Pharma, grants and other support from Exilixis, and other support from Erytech, Incyte, Bayer, and Adaptimmune outside the submitted work. Dr Neely reported personal fees from Bristol Myers Squibb outside the submitted work. Dr Shen reported being an employee of Bristol Myers Squibb. Dr Wisniewski reported other support from Bristol Myers Squibb during the conduct of the study; other suport from Bristol Myers Squibb outside the submitted work; and stock ownership in Bristol Myers Squibb as an employee of the company. Dr Anderson reported other support from Bristol Myers Squibb during the conduct of the study and other support from Bristol Myers Squibb outside the submitted work. Dr Hsu reported grants and personal fees from Bristol Myers Squibb and Ono Pharmaceutical during the conduct of the study; grants from Roche and Ipsen, and personal fees from AstraZeneca, Bayer, Eisai, Eli Lilly, Ipsen, Merck Serono, Merck Sharp & Dohme, Novartis, Roche, and TTY Biopharm outside the submitted work. No other disclosures were reported.
                Funding/Support: This study was supported by Bristol Myers Squibb (Princeton, New Jersey) and Ono Pharmaceutical (Osaka, Japan).
                Role of the Funder/Sponsor: The authors designed the study in collaboration with the funder (Bristol Myers Squibb). The funder gathered and analyzed the data with the authors.
                Meeting Presentation: Presented in part at the American Society of Clinical Oncology; Chicago, Illinois; May 31-June 4, 2019.
                Data Sharing Statement: See Supplement 3.
                Additional Contributions: The authors would like to thank the patients who participated in this trial and their families; the investigators, study coordinators, study teams, and nurses who assisted; and Dako, an Agilent Technologies company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay. We acknowledge Christine Dela Cruz, MD, MHScM, for her contributions to the CheckMate 040 study, including study design, protocol development, and analysis and interpretation of data, while she was an employee of Bristol Myers Squibb. We acknowledge Steve Blum, MBA, MA, and Gwilym Thompson, PhD, employees of Bristol Myers Squibb, for their analysis and interpretation of patient-reported outcomes data; we also thank Fiona Taylor, MBiochem, Christine Yip, MPP, and Rachel Lawrence, CStat, from Adelphi Values, a consulting firm that received payment from Bristol Myers Squibb to conduct patient-reported outcome analyses for Bristol Myers Squibb, for the support provided in the analysis of the patient-reported outcomes data. Writing and editorial assistance was provided by Emily Bruce, PhD, of Parexel International (Waltham, Massachusetts), funded by Bristol Myers Squibb.
                Article
                coi200072
                10.1001/jamaoncol.2020.4564
                7530824
                33001135
                7f650839-8051-4114-a114-38ce84239a54
                Copyright 2020 Yau T et al. JAMA Oncology.

                This is an open access article distributed under the terms of the CC-BY-NC-ND License.

                History
                : 6 April 2020
                : 17 July 2020
                Funding
                Funded by: Bristol Myers Squibb
                Funded by: Ono Pharmaceutical
                Categories
                Research
                Research
                Original Investigation
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                Online Only
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