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Background & Aims: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status., Methods: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0., Results: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC., Conclusions: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC., Lay Summary: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population., Clinical Trial Number: NCT01658878., Competing Interests: Conflict of interest MK reports receiving personal fees from Bristol Myers Squibb, Bayer, Eisai, MSD, and Ono Pharmaceutical Co., Ltd., and receiving grants from Eisai, Otsuka, Taiho Pharmaceutical, EA Pharma, Takeda, AbbVie, and Gilead Sciences. AM reports receiving personal fees from Bayer, BTG, and Bristol Myers Squibb and receiving grants and other funding from Bayer. AS reports receiving personal fees from Bristol Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Takeda, Roche, AbbVie, Amgen, Celgene, ArQule, Lilly, Sandoz, and Novartis. IM reports receiving personal fees from Alligator Bioscience, Bristol Myers Squibb, EMD Serono, F-Star Biotechnology, Genmab, Roche, Bayer, MSD, Numab, Lilly, AstraZeneca/MedImmune, Incyte, and Tusk Therapeutics and receiving grants from Pfizer, Alligator Bioscience, Bristol Myers Squibb, and Roche. SP reports receiving personal fees from Celgene, Novartis, Eisai, Bristol Myers Squibb, Shire, and Sirtex Medical; receiving grants from Bristol Myers Squibb; and receiving non-financial support from Bristol Myers Squibb, Amgen, and Merck. ABE reports receiving personal fees from CytomX Therapeutics, Bristol Myers Squibb, Bayer, Eisai, Roche/Genentech, EMD Serono, Exelixis, Pieris Pharmaceuticals, Agenus, and Merck and receiving grants from AstraZeneca, Merck, and Astex Pharmaceuticals. RK reports receiving research funding from Bristol Myers Squibb, Eisai, Ono Pharmaceutical Co., Ltd., MSD KK, AstraZeneca plc, EA Pharma Co., Ltd, Takeda Pharmaceutical Company Limited, CHUGAI Pharmaceutical Co, LTD and honoraria from MSD, Mitsubishi Tanabe Pharma Corporation, Shionogi & Co., Ltd, GE Healthcare Japan, Daiichi Sankyo Company, Limited. BE reports receiving personal fees from Bayer, Lexicon, RTI Health Solutions, BTG, Loxo, Merrimack, and Bristol Myers Squibb; receiving grants from AVEO, Boston Biomedical, Bristol Myers Squibb, Cleave Biosciences, Five Prime Therapeutics, Genentech, Hoosier Cancer Research Network, ICON Clinical Research, Merck, Novartis, Pfizer, PPD, Taiho Pharmaceutical, Xencor, and AstraZeneca/MedImmune; and receiving other funding from Exelixis and ERYTECH Pharma. YI reports receiving personal fees from Gilead Sciences Inc, AbbVie Inc, Merck Sharp & Dohme, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd., funding from Takeda Pharmaceutical Company Limited, EA Pharma Co, Ltd, Eisai Co Ltd, AbbVie Inc, Merck Sharp & Dohme, Bayer Yakuhin Ltd, Bristol Myers Squibb, Astellas Pharma Inc, Nissan Chemical Industries, Ltd, FUJIREBIO Inc, Ono Pharmaceutical Co., Ltd., Gilead Sciences Inc, and Nichinichi Pharmaceutical Co Ltd. MR reports receiving personal fees from Bayer, Bristol Myers Squibb, AstraZeneca, Ipsen, Lilly, BTG, and Roche; receiving grants from Bayer and Lilly; and receiving non-financial support from Bayer and Bristol Myers Squibb. YS reports receiving personal fees from Bristol Myers Squibb; and receiving other funding from Bristol Myers Squibb and Sanofi. JN reports receiving personal fees and other funding from Bristol Myers Squibb. JA reports receiving personal fees and other funding from Bristol Myers Squibb. TW reports receiving personal fees, grants, and other funding from Bristol Myers Squibb. BS has served in a consulting or advisory role for Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, TERUMO, H3 Biomedicine, Ipsen, Lilly, and Roche; has served on speakers’ bureaus for Bayer, Bristol Myers Squibb, Sirtex Medical, TERUMO, and Ipsen; and has received research funding from Bristol Myers Squibb and Sirtex Medical. ACG, MA, KN, FD, and OC report no disclosures. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC., Methods: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS])., Results: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 ≥1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01)., Conclusions: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC., Lay Summary: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer., Nct Number: NCT01658878., Competing Interests: Conflicts of interest GA has served in a consulting or advisory role for Agios, AstraZeneca, Autem, Bayer, BeiGene, Berry Genomics, Celgene, CytomX, Debiopharm, Eisai, Eli Lilly, Flatiron Health, Genentech/Roche, Gilead, Incyte, Ipsen, LAM, Loxo, Merck, Minapharm Pharmaceuticals, Polaris, QED Therapeutics, RedHill, Silenseed, SillaJen, Sobi, TheraBionic, twoXAR, Vector, Yiviva. GA has also received grants/research support from Acta Biologica, Agios, AstraZeneca, Bayer, BeiGene, Berry Genomics, Bristol Myers Squibb, CASI, Celgene, Exelixis, Genentech/Roche, Halozyme, Incyte, MabVax, Puma, QED Therapeutics, SillaJen, Yiviva. GA has a patent pending, titled ‘Articles and methods for preventing and treating dermatologic adverse events’, identified by international patent application no. PCT/US2014/031545 filed on March 24, 2014, and priority application no. 61/804,907. AC has served in a consulting or advisory role for Bayer, Bristol Myers Squibb, Eisai, Merck Serono, Novartis, ONO, and Onxeo. AC has also received speaking support from Novartis and has served in a consulting or advisory role for Bayer, Bristol Myers Squibb, Eisai, Merck Serono, Novartis, ONO, and Onxeo. AEK has served in a consulting or advisory role for Agenus, Bayer, Bristol Myers Squibb, CytomX, Eisai, EMD Serono, Exelixis, Genentech, Merck, Pieris, and Roche. AEK has also received grants/research support from Astex and Merck. JF has served in a consulting or advisory role for Asahi Kasei, Astellas, AstraZeneca, Bayer Yakuhin, Chugai Pharma, Daiichi Sankyo, EA Pharma, Eisai, Fujifilm, J-Pharma, Kyowa Hakko Kirin, Lilly Japan, Merck Serono, Mochida, MSD, Nippon Kayaku, Novartis, ONO, Otsuka, Pfizer, Sandoz, Sanofi, Sawai, Shionogi, Shire, Sumitomo Dainippon Pharma, Taiho, Takeda, Yakult Honsha, and Zeria. JF has also received grant/research support from Chugai Pharma, Daiichi Sankyo, Eisai, J-Pharma, Janssen, Kyowa Hakko Kirin, Lilly Japan, Merck Serono, Mochida, MSD, NanoCarrier Co, Novartis, OncoTherapy Science, ONO, Shionogi, Sumitomo Dainippon Pharma, Taiho, Takeda, Yakult Honsha, and Zeria. RF has served as a consultant for and received institutional grant support from Bristol Myers Squibb during the conduct of this study. RF has also served in a consultant role for Bayer, Eisai, Lilly, Merck, Novartis, and Pfizer. IM has served in a consulting or advisory role for Alligator Bioscience, AstraZeneca, Bayer, Bristol Myers Squibb, EMD Serono, F-star Biotechnology, Genmab, MSD, Lilly, MedImmune, Numab, Roche, and Tusk Therapeutics. IM has received grant/research support from Alligator Bioscience, Bristol Myers Squibb, Pfizer, and Roche, and other forms of compensation, including travel accommodations and expenses, from Bristol Myers Squibb, Incyte, MSD, and Roche. JP has served in a consulting or advisory role for Bayer, Bristol Myers Squibb, Eisai, Midatech, ONO, and Roche and received honoraria from Bayer and Eisai. JP has also received grant/research support from AstraZeneca, Blueprint, Bristol Myers Squibb, Eisai, Exelixis, Kowa, ONO, and Roche. BS has served in a consulting or advisory role for Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Ipsen, Lilly, Merck, Onxeo, Roche, and Sirtex Medical. BS has also received grant/research support from Bristol Myers Squibb, Onxeo, and Sirtex Medical, and speaking support from Bayer, Bristol Myers Squibb, and Sirtex Medical. TY has served in a consulting or advisory role for Bristol Myers Squibb. ZB has a patent pending for the 4-gene inflammatory signature, identified by international patent application no. PCT/US2020/025441. JN, HT, and MT are Bristol Myers Squibb employees and stockholders. SW and ZB were employees of Bristol Myers Squibb at the time this study was conducted, and SW is a Bristol Myers Squibb stockholder. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: 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., Methods: 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., Findings: 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., Interpretation: 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., Funding: Bristol-Myers Squibb., (Copyright © 2017 Elsevier Ltd. All rights reserved.)