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Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

  • Author Footnotes
    ∗ contributed equally
    Bernhard Scheiner
    Footnotes
    ∗ contributed equally
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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    ∗ contributed equally
    Daniel Roessler
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    ∗ contributed equally
    Affiliations
    Department of Medicine II, University Hospital, LMU Munich, Munich, 81377, Germany
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  • Samuel Phen
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    Department of Medicine, UT Southwestern Medical Center, Dallas TX USA
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  • Mir Lim
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    Department of Medicine, UT Southwestern Medical Center, Dallas TX USA
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  • Katharina Pomej
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Tiziana Pressiani
    Affiliations
    Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy
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  • Antonella Cammarota
    Affiliations
    Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy

    Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele (Milan), Italy
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  • Thorben W. Fründt
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    1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Johann von Felden
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    1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Kornelius Schulze
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    1. Department of Internal Medicine, Gastroenterology & Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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  • Vera Himmelsbach
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    Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
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  • Fabian Finkelmeier
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    Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt/Main, Germany
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  • Ansgar Deibel
    Affiliations
    Department of Hepatology and Gastroenterology, University Hospital Zurich and University Zurich, Zurich, Switzerland
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  • Alexander R. Siebenhüner
    Affiliations
    Department of Medical Oncology and Hematology, University Hospital Zurich and University Zurich, Zurich, Switzerland

    Department of Medical Oncology and Hematology, Cantonal Hospital Schaffhausen, Schaffhausen, Switzerland
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  • Kateryna Shmanko
    Affiliations
    Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • Pompilia Radu
    Affiliations
    Hepatology-Department of Biomedical Research, University of Bern, Bern, Switzerland

    Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
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  • Birgit Schwacha-Eipper
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    Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
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  • Matthias P. Ebert
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    Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
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  • Andreas Teufel
    Affiliations
    Clinical Cooperation Unit Healthy Metabolism, Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Department of Internal Medicine II, Division of Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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  • Angela Djanani
    Affiliations
    Department of Internal Medicine I, Division of Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck Austria
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  • Florian Hucke
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    Internal Medicine and Gastroenterology (IMuG), including Centralized Emergency Service (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
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  • Lorenz Balcar
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Alexander B. Philipp
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    Department of Medicine II, University Hospital, LMU Munich, Munich, 81377, Germany
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  • David Hsiehchen
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    Department of Medicine, UT Southwestern Medical Center, Dallas TX USA
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  • Marino Venerito
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    Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von Guericke University Hospital, 39120 Magdeburg, Germany
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  • Friedrich Sinner
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    Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von Guericke University Hospital, 39120 Magdeburg, Germany
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  • Michael Trauner
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Antonio D'Alessio
    Affiliations
    Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele (Milan), Italy

    Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
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  • Claudia A.M. Fulgenzi
    Affiliations
    Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK

    Department of Medical Oncology, University Campus Bio-Medico of Rome, Italy
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  • David J. Pinato
    Affiliations
    Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK

    Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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  • Markus Peck-Radosavljevic
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    Internal Medicine and Gastroenterology (IMuG), including Centralized Emergency Service (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
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  • Jean-François Dufour
    Affiliations
    Hepatology-Department of Biomedical Research, University of Bern, Bern, Switzerland
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  • Arndt Weinmann
    Affiliations
    Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
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  • Andreas E. Kremer
    Affiliations
    Department of Hepatology and Gastroenterology, University Hospital Zurich and University Zurich, Zurich, Switzerland

    Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
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  • Amit G. Singal
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    Department of Medicine, UT Southwestern Medical Center, Dallas TX USA
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  • Enrico N. De Toni
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    Department of Medicine II, University Hospital, LMU Munich, Munich, 81377, Germany
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  • Author Footnotes
    ∗ contributed equally
    Lorenza Rimassa
    Footnotes
    ∗ contributed equally
    Affiliations
    Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano (Milan), Italy

    Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele (Milan), Italy
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  • Author Footnotes
    ∗ contributed equally
    Matthias Pinter
    Correspondence
    Corresponding author. , Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria, P: +43 1 40400 47440, F: +43 1 40400 47350,
    Footnotes
    ∗ contributed equally
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Liver Cancer (HCC) Study Group Vienna, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
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  • Author Footnotes
    ∗ contributed equally
Open AccessPublished:October 26, 2022DOI:https://doi.org/10.1016/j.jhepr.2022.100620

      Highlights:

      • Immune checkpoint inhibitor (ICI) rechallenge is uncommon in clinical practice – we screened 994 patients at 14 institutions and identified 58 patients rechallenged with an ICI-based regimen
      • Objective radiological response rate, disease control rate, as well as median time to progression were comparable between first and second ICI-based treatment
      • Objective responses were also observed in patients with progressive disease as best radiological response during first ICI-based treatment as well as in patients receiving atezolizumab/bevacizumab as prior ICI regimen
      • ICI rechallenge was safe in our cohort and high-grade (grade 3-4) treatment-related adverse events were uncommon

      Abstract

      Background & Aims

      We investigated efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line.

      Methods

      In this international, retrospective multicenter study, patients with HCC who received at least 2 lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. Main outcomes included best overall response (BOR) and treatment-related adverse events.

      Results

      Of 994 ICI-treated HCC patients screened, a total of 58 patients (male, n=41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n=26, 45%; ICI-2, n=4, 7%), dual ICI regimens (n=1, 2%; n=12, 21%), or ICI combined with targeted therapies/anti-VEGF (n=31, 53%; n=42, 72%). Most patients discontinued ICI-1 due to progression (n=52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as BOR at ICI-1 (n=11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95%CI, 3.0-7.7) months and 5.2 (95%CI, 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively.

      Conclusions

      ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of HCC patients. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials.

      Lay summary

      Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as all available second-line treatment options have not been studied in immunotherapy-pretreated patients. Particularly, the role of ICI re-challenge in HCC patients is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in HCC patients pretreated with immunotherapy in a retrospective, international, multicenter study.

      Graphical abstract

      Keywords

      Data availability statement

      The data that support the findings of this study are available from the corresponding author, MP, upon reasonable request.

      Potential conflicts of interest

      BS received travel support from AbbVie, Ipsen and Gilead.
      DR has received advisory fees from Bayer and speakers fees as well as travel grants from Ipsen. He is an investigator for Bayer, BMS, Lilly, AstraZeneca and Roche.
      SP has nothing to disclose.
      ML has nothing to disclose.
      KP has nothing to disclose.
      TP received consulting fees from IQVIA and Bayer; and institutional research funding from Lilly, Roche, Bayer.
      AC has nothing to disclose.
      TWF has nothing to disclose.
      JVF has received advisory board fees from Roche.
      KS served as consultant for Ipsen and Bayer, and conducts studies for Bayer, Roche, Lilly, MSD, and BMS.
      VH has nothing to disclose.
      FF received travel support from Abbvie and Novartis, and speaker fees from Abbvie and MSD.
      AD has nothing to disclose.
      ARS has served at advisory boards and received consulting honoraria from AMGEN, AAA, Bayer, BMS, IPSEN, Lilly, Merck, MSD, Pfizer, Roche, Sanofi, and Servier.
      KS has nothing to disclose.
      PR has nothing to disclose.
      BiS has nothing to disclose.
      MPE received consulting honoraria from BMS and MSD.
      AT received consulting honoraria and/or lecture fees from Bayer, IPSEN, Lilly, BMS, Eisai Novartis, Roche, Intercept, Falk, AbbVie, and Gilead. He received travel grants from IPSEN, AbbVie, and Gilead. He is an investigator for IPSEN and GILEAD.
      AngD received advisory board fees from Roche and BMS, and travel support from Roche and Ipsen.
      FH received travel support from Bayer, Abbvie, and Gilead.
      LB has nothing to disclose.
      ABP has nothing to disclose.
      DH received research support from Pfizer.
      MV received speaker fees from Nordic Pharma, Ipsen, Merck Serono, Bayer Vital, Lilly, AstraZeneca, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), and Sirtex, advisory board fees from Roche, Ipsen, Lilly, Nordic Pharma, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Eisai, AstraZeneca and Amgen, research grants from Sirtex.
      FS has nothing to disclose.
      MT received speaker fees from Bristol-Myers Squibb (BMS), Falk Foundation, Gilead, Intercept and Merck Sharp & Dohme (MSD); advisory board fees from Abbvie, Albireo, Boehringer Ingelheim, BiomX, Falk Pharma GmbH, GENFIT, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Regulus and Shire; travel grants from AbbVie, Falk, Gilead, and Intercept; and research grants from Albireo, CymaBay, Falk, Gilead, Intercept, MSD, and Takeda. He is also coinventor of patents on the medical use of norUDCA filed by the Medical University of Graz.
      ADA received travel support and consultancy fees from Roche.
      CAMF has nothing to disclose.
      DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra, Mursla, Exact Sciences and Astra Zeneca; research funding (to institution) from MSD and BMS.
      MPR is advisor/consultant for Astra Zeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he served as a speaker for Bayer, Eisai, Ipsen, Lilly, and Roche; he is an investigator for Bayer, BMS, Eisai, Exelixis, Lilly, and Roche.
      JFD received compensations as a member of scientific advisory boards of Abbvie, Bayer, Bristol–Myers Squibb, Falk, Galapagos, Genfit, Genkyotex, Gilead Sciences, HepaRegenix, Intercept, Lilly, Merck, and Novartis.
      AW received compensations as a member of scientific advisory boards for BMS, Wako and Sanofi. He served as a speaker for Leo Pharma, Eisai, Ipsen and Roche and received travel support from Merck and Servier.
      AEK has received consulting fees from Abbvie, AstraZeneca, Bayer, CymaBay, Escient, FMC, Gilead, GSK, Guidepoint, Intercept, Mirum, Medscape, MSD, Myr, Viofor; lecture fees from Abbvie, AOP Orphan, Bayer, BMS, CMS, CymaBay, Eisai, Falk, Gilead, GSK, Intercept, Janssen, Newbridge, Novartis, Lilly, MSD, Zambon; and institutional research funding from Intercept.
      AGS served on advisory boards and as a consultant for Genentech, AstraZeneca, Eisai, Bayer, Exelixis, TARGET RWE, FujiFilm Medical Sciences, Glycotest, Exact Sciences, GRAIL, and Freenome.
      ENDT has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, MSD, Mallinckrodt, Omega, Pfizer, IPSEN, Terumo and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, Astrazeneca, BMS, Bayer, Celsion and Roche, and lecture honoraria from BMS and Falk. He has received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and IPSEN and Roche.
      LR has received consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, Zymeworks; lectures fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi, Servier; travel expenses from AstraZeneca; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks.
      MP is an investigator for Bayer, BMS, Eisai, Ipsen, Lilly, and Roche; he received speaker honoraria from Bayer, BMS, Eisai, Lilly, MSD, and Roche; he is a consultant for Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he received travel support from Bayer, BMS, and Roche.

      Funding

      D.J.P. acknowledges the infrastructural support provided by Imperial Experimental Cancer Medicine Centre, Cancer Research UK Imperial Centre, the Imperial College BRC and the Imperial College Healthcare NHS Trust Tissue Bank.

      Author contributions

      All authors contributed either to research design (B.S. and M.P.), and/or the data acquisition (B.S., D.R., S.P., M.L., K.P., T.P., A.C., T.W.F., J.v.F., K.S., V.H., F.F., A.D., A.R.S., K.S., P.R., Bi.S., M.P.E., A.T., Ang.D., F.H., L.B., A.B.P., D.H., M.V., F.S., M.T., A.D’A., C.A.M.F., D.J.P., M.P.-R., J.-F.D., A.W., A.E.K., A.G.S., E.N.d.T., L.R., M.P.), analysis (B.S. and M.P.), or interpretation (all authors) of data. B.S. and M.P. drafted the manuscript, which was critically revised by all other authors.

      Clinical trial number

      N/A.

      Introduction

      Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer-related mortality worldwide
      • Sung H.
      • Ferlay J.
      • Siegel R.L.
      • Laversanne M.
      • Soerjomataram I.
      • Jemal A.
      • et al.
      Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
      . Most patients become candidates for systemic therapy at some point during the course of the disease. The systemic treatment landscape of HCC has changed rapidly over the last years
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma: An EASL position paper.
      . Several immune checkpoint inhibitors (ICIs) have been added to the treatment armamentarium in the United States after receiving conditional approval for sorafenib-pretreated patients following promising phase II data
      • Pinter M.
      • Jain R.K.
      • Duda D.G.
      The Current Landscape of Immune Checkpoint Blockade in Hepatocellular Carcinoma: A Review.
      . The combination of atezolizumab/bevacizumab was the first ICI-based regimen to meet its primary survival endpoints versus sorafenib in a phase III trial, and consequently became the standard of care in systemic front-line treatment
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma: An EASL position paper.
      ,
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.
      ,
      • Gordan J.D.
      • Kennedy E.B.
      • Abou-Alfa G.K.
      • Beg M.S.
      • Brower S.T.
      • Gade T.P.
      • et al.
      Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline.
      . Only recently, the combination of durvalumab/tremelimumab was superior to sorafenib in terms of overall survival in a phase III trial, and durvalumab alone was non-inferior to sorafenib

      Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evidence.0(0):EVIDoa2100070.

      ; thus, both will likely be added as additional first-line options upon approval
      • Reig M.
      • Forner A.
      • Rimola J.
      • Ferrer-Fabrega J.
      • Burrel M.
      • Garcia-Criado A.
      • et al.
      BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update.
      .
      Sequencing after first-line immunotherapy is currently empirical in HCC and largely based on clinical characteristics and toxicity profiles, as well as local regulations and drug availabilities
      • Bruix J.
      • Chan S.L.
      • Galle P.R.
      • Rimassa L.
      • Sangro B.
      Systemic treatment of hepatocellular carcinoma: An EASL position paper.
      ,
      • Kirstein M.M.
      • Scheiner B.
      • Marwede T.
      • Wolf C.
      • Voigtländer T.
      • Semmler G.
      • et al.
      Sequential systemic treatment in patients with hepatocellular carcinoma.
      . The role of subsequent ICI use in ICI-pretreated HCC patients is unclear, as data from prospective trials are lacking. Successful ICI rechallenge in a subset of patients has been reported in other solid tumors, including melanoma
      • Ribas A.
      • Puzanov I.
      • Dummer R.
      • Schadendorf D.
      • Hamid O.
      • Robert C.
      • et al.
      Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.
      and renal cell carcinoma
      • Ravi P.
      • Mantia C.
      • Su C.
      • Sorenson K.
      • Elhag D.
      • Rathi N.
      • et al.
      Evaluation of the Safety and Efficacy of Immunotherapy Rechallenge in Patients With Renal Cell Carcinoma.
      ,
      • Gul A.
      • Stewart T.F.
      • Mantia C.M.
      • Shah N.J.
      • Gatof E.S.
      • Long Y.
      • et al.
      Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors.
      , providing the rationale for evaluating this strategy also in HCC patients.
      In this international, retrospective, multicenter study, we investigated the efficacy and safety of ICI-based regimens in patients with HCC who had received ICIs in a previous line of systemic therapy.

      Methods

      Patients

      In this international, retrospective multicenter study, patients with histologically or radiologically diagnosed HCC who received at least 2 lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions in Austria, Germany, Italy, Switzerland, United Kingdom, and the United States were considered. Patients who received 2 lines of different ICIs alone or as combination therapy and patients who received the same ICI at ICI-1 and ICI-2 but with a different combination partner were eligible. Patients were allowed to receive one or more treatments between ICI-1 and ICI-2.
      Patients who received ICIs in a curative setting as (neo)adjuvant treatment before/after resection or ablation, and patients who received loco-regional therapies as the main treatment but in combination with ICIs were not included. The retrospective analysis was approved by the Ethics Committee of the Medical University of Vienna.

      Assessments and outcomes

      Main outcomes included investigator-assessed best overall response (BOR) and treatment-related adverse events (TRAEs) according to Common Terminology Criteria for Adverse Events version 5.0. Objective response rate (ORR) was defined as the proportion of patients with complete or partial response as BOR. Disease control rate (DCR) was defined as the proportion of patients achieving complete/partial response or stable disease as BOR. Further outcomes included time to progression (TTP) as well as overall survival (OS).

      Statistics

      Data on baseline characteristics, radiological tumor evaluation, and TRAEs were summarized using descriptive statistics. Median duration of treatment was defined as time from the date of treatment initiation until the date of last administration; patients who were still receiving immunotherapy at data cut-off were censored. Patients who had at least one follow-up imaging were evaluable for assessment of BOR and TTP. TTP was defined as the time from the date of treatment initiation until the date of first radiologically confirmed tumor progression; patients without radiologically confirmed tumor progression were censored at the date of last imaging. OS was defined as the time from treatment start until date of death; patients who were still alive were censored at the date of last contact. Survival curves were calculated using the Kaplan-Meier method. Statistical analyses were performed using IBM SPSS Statistics version 26.0 (SPSS Inc., Chicago, IL). Figure 1 was created using the software sankeyMATIC freely available at https://sankeymatic.com and Figure 2 was created using GraphPad Prism 9 (GraphPad Software, LLC, San Diego, US). Median follow-up time was calculated using the reverse Kaplan-Meier method.
      Figure thumbnail gr1
      Figure 1Type of immune checkpoint inhibitor regimen used at first and second line of ICI treatment. Abbreviations: ICI, immune checkpoint inhibitor; ICI-1, first line of ICI treatment; ICI-2, second line of ICI treatment; TT, targeted therapy, VEGF, vascular endothelial growth factor.
      Figure thumbnail gr2
      Figure 2Best overall response (BOR) at first (ICI-1) and second (ICI-2) line of ICI treatment in selected patient populations. (A) BOR at ICI-1 according to type of therapy received at ICI-1, (B) BOR at ICI-2 according to type of therapy received at ICI-2, and (C) BOR at ICI-2 according to BOR at ICI-1. Abbreviations: CR, complete response; ICI, immune checkpoint inhibitor; ICI-1, first line of ICI treatment; ICI-2, second line of ICI treatment; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease; TT, targeted therapy, VEGF, vascular endothelial growth factor.

      Results

      Patients

      Of 994 ICI-treated HCC patients screened, 58 (6%) patients were put on another ICI-based regimen between March 2019 and March 2022 after prior ICI discontinuation and included in this analysis. Detailed patient characteristics at start of ICI-1 and ICI-2 are displayed in Table 1. Most patients had well-preserved liver function (Child-Pugh A) at ICI-1 (n=55, 95%) and ICI-2 (n=50, 86%). The majority had BCLC stage C at ICI-1 (n=44, 76%) and ICI-2 (n=48, 83%). Forty-two (72%) patients received any prior HCC treatment before immunotherapy. Most patients received ICI-1 as first (n=36, 62%) and ICI-2 as second (n=29, 50%) line of systemic therapy. Seventeen patients (29%) received at least one systemic line between ICI-1 and ICI-2. ICI-based regimens used at ICI-1 and ICI-2 are shown in Supplemental Table 1 and Figure 1. Fifty-two patients (90%) discontinued ICI-1 due to radiological progression, 4 (7%) because of adverse events, one (2%) due to clinical progression, and another one (2%) due to patient preference. Median duration of ICI-1 and ICI-2 was 5.4 (95%CI, 4.3-6.5) months and 3.6 (95%CI, 2.4-4.9) months, respectively. Median duration from ICI-1 discontinuation to ICI-2 initiation was 1.3 (95%CI, 0.4-2.1) months.
      Table 1Patient characteristics at ICI-1 and ICI-2.
      ICI-1 (n=58; 100%)ICI-2 (n=58; 100%)
      Age (years), mean±SD65.0±9.068.2±9.4
      Sex
      Male41 (71%)
      Etiology
      viral24 (41%)
      Child-Pugh stage
      A55 (95%)50 (86%)
      B2 (3%)8 (14%)
      C1 (2%)0
      ECOG PS
      missing ICI-1: n=1;
      ≥110 (17%)24 (41%)
      Treatment prior to ICI-1
      Surgery25 (43%)
      Ablation7 (12%)
      Loco-regional (TACE, SIRT, radiation)20 (34%)
      Systemic22 (38%)
      Macrovascular invasion21 (36%)21 (36%)
      Extrahepatic metastases29 (50%)34 (59%)
      BCLC stage
      B13 (22%)10 (17%)
      C44 (76%)48 (83%)
      D1 (2%)0
      Alpha-Fetoprotein (IU/mL)
      missing ICI-1: n=2 and ICI-2: n=4;
      Median (IQR)54.3 (5.7-902.2)182.2 (5.8-7907.4)
      Line of ICI therapy
      Median (range)1 (1-4)3 (2-9)
      Type of ICI regimen
      ICI alone26 (45%)4 (7%)
      Dual ICI combination1 (2%)12 (21%)
      ICI plus TT/anti-VEGF31 (53%)42 (72%)
      Reason for discontinuation of ICI-1
      Radiological progression52 (90%)
      Toxicity4 (7%)
      Other2 (3%)
      Abbreviations: BCLC, Barcelona-Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ICI, immune checkpoint inhibitor; ICI-1, first line of ICI treatment; ICI-2, second line of ICI treatment; TACE, transarterial chemoembolization; TT, targeted therapy; VEGF, vascular endothelial growth factor; SIRT, selective internal radiotherapy;
      missing ICI-1: n=1;
      ∗∗ missing ICI-1: n=2 and ICI-2: n=4;

      Efficacy

      Median estimated follow-up from ICI-1 was 25.1 (95%CI, 20.8-29.4) months. Twenty-six patients (45%) died during the observation period. Median OS from initiation of systemic first-line, start of ICI-1, and start of ICI-2 was 47.0 (95%CI, 39.9-54.2) months, 39.8 (95%CI, 33.7-45.9) months, and 12.0 (95%CI, 7.5-16.5) months, respectively. BOR at ICI-1 was complete response (CR)/partial response (PR)/stable disease (SD)/ progressive disease (PD)/not evaluable (NE) in 0 (0%)/ 13 (22%)/ 21 (36%)/ 21 (36%)/ 3 (5%) patients, corresponding to an ORR and DCR of 22% and 59%, respectively. BOR at ICI-2 was CR/PR/SD/PD/NE in 1 (2%)/ 14 (24%)/ 17 (29%)/ 17 (29%)/ 9 (16%) patients; ORR and DCR were 26% and 55%, respectively (Table 2). One patient (2%) had an objective response at both ICI-1 and ICI-2.
      Table 2Main efficacy outcomes at ICI-1 and ICI-2.
      ICI-1ICI-2
      Best overall response
      CR01 (2%)
      PR13 (22%)14 (24%)
      SD21 (36%)17 (29%)
      PD21 (36%)17 (29%)
      N/E3 (5%)9 (16%)
      ORR (CR+PR)13 (22%)15 (26%)
      DCR (CR+PR+SD)34 (59%)32 (55%)
      TTP, median (95%CI)5.4 (3.0-7.7) months5.2 (3.3-7.0) months
      Abbreviations: CR, complete response; DCR, disease control rate; ICI-1, first line of ICI treatment; ICI-2, second line of ICI treatment; N/E, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; TTP, time to progression
      Median TTP was 5.4 (95%CI, 3.0-7.7) months (ICI-1) and 5.2 (95%CI, 3.3-7.0) months (ICI-2), respectively (Table 2). Responses at ICI-2 were also seen in patients who had progressive disease as BOR at ICI-1 (n=11/21; 52%), and who received ICI monotherapy at ICI-2 (n=2/4; 50%) (Figure 2). Characteristics of individual patients who achieved a complete or partial response at ICI-2 are displayed in Table 3.
      Table 3Details of patients with a response at ICI-2.
      Patient #Type of ICI-1Line of ICI-1BOR at ICI-1Reason for discontinuation of ICI-1Time between ICI-1 and ICI-2 (months)Type of ICI-2Line of ICI-2BOR at ICI-2
      1Pembrolizumab3PRProgression5.4Atezolizumab/bevacizumab6PR
      2Atezolizumab/bevacizumab1N/EAdverse event0.5Pembrolizumab2CR
      3Nivolumab2PDAdverse event0.9Pembrolizumab3PR
      4Pembrolizumab4PDProgression6.5Atezolizumab/bevacizumab6PR
      5Pembrolizumab1PDProgression3.3Atezolizumab/bevacizumab2PR
      6Nivolumab3PDProgression22.8Atezolizumab/bevacizumab6PR
      7Pembrolizumab1PDProgression1.1Atezolizumab/bevacizumab2PR
      8Pembrolizumab2PDProgression5.6Pembrolizumab/lenvatinib4PR
      9Nivolumab2PDProgression18.8Atezolizumab/bevacizumab4PR
      10Nivolumab/lenvatinib1SDAdverse event0.5Nivolumab/ipilimumab2PR
      11Atezolizumab/bevacizumab2PDProgression0.7Nivolumab/ipilimumab3PR
      12Nivolumab/lenvatinib1PDProgression0.5Nivolumab/ipilimumab2PR
      13Atezolizumab/Bevacizumab2PDProgression10.2Nivolumab/ipilimumab5PR
      14Pembrolizumab/bavituximab1PDProgression1.1Pembrolizumab/bevacizumab2PR
      15Pembrolizumab/bavituximab1N/EPatient’s preference0.7Atezolizumab/bevacizumab2PR
      Abbreviations: BOR, best overall response; CR, complete response; ICI-1, first line of ICI treatment; ICI-2, second line of ICI treatment; N/E, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease
      In the subgroup of patients receiving atezolizumab/bevacizumab at ICI-1 (n=17; 29%), 2 (12%) and 15 (88%) patients were treated with ICI monotherapy and combinatorial regimens at ICI-2, respectively (Supplemental Table 2). The ORR and DCR at ICI-2 in this subgroup were 18% (n=3) and 53% (n=9), respectively. In patients who were treated with atezolizumab/bevacizumab at ICI-2 (n=29; 50%), ORR and DCR were 24% (n=7) and 52% (n=15), respectively.

      Safety

      In total, 31 (53%) patients developed at least one TRAE at ICI-1 and 28 (48%) patients at ICI-2, respectively; grade 3-4 TRAEs were observed in 9 (16%) and 10 (17%) patients at ICI-1 and ICI-2, respectively. Three patients (5%) experienced grade 3-4 TRAEs at both ICI-1 and ICI-2. No treatment-related deaths were recorded. Eight (14%) and 7 (12%) required systemic corticosteroid treatment at ICI-1 and ICI-2, respectively, and 1 patient (2%) received systemic corticosteroids at both ICI-1 and ICI-2. Four (7%) and 2 (3%) patients discontinued treatment due to toxicity at ICI-1 and ICI-2, respectively. TRAEs at ICI-1 and ICI-2 are summarized in Table 4.
      Table 4Treatment-related adverse events at ICI-1 and ICI-2.
      ICI-1ICI-2
      Any gradeGrade 3-4
      No grade 5 treatment-related adverse events were recorded.
      Any gradeGrade 3
      No grade 4 or 5 treatment-related adverse events were recorded.
      Infusion/allergic reaction6 (10%)1 (2%)
      Arthritis/arthralgia/myalgia5 (9%)4 (7%)
      Diarrhea/colitis4 (7%)1 (2%)6 (10%)1 (2%)
      Pruritus4 (7%)2 (3%)
      Mucositis/stomatitis2 (3%)1 (2%)2 (3%)1 (2%)
      Hepatitis2 (3%)4 (7%)3 (5%)
      Dermatological3 (5%)4 (7%)1 (2%)
      Arterial hypertension6 (10%)2 (3%)3 (5%)1 (2%)
      Transient ischemic attack1 (2%)1 (2%)
      Scrotal edema1 (2%)1 (2%)
      Amylase/lipase increase1 (2%)1 (2%)
      Proteinuria1 (2%)1 (2%)1 (2%)1 (2%)
      Nephritis1 (2%)
      Cough1 (2%)
      Sinusitis1 (2%)
      Thrombocytopenia2 (3%)
      Hypertriglyceridemia1 (2%)
      Palmar-plantar erythrodysesthesia1 (2%)2 (3%)1 (2%)
      Fatigue3 (5%)9 (16%)1 (2%)
      Epistaxis1 (2%)1 (2%)
      AV block III°1 (2%)1 (2%)
      Wound healing impairment1 (2%)
      Hair loss2 (3%)1 (2%)
      Nausea1 (2%)
      Gastritis1 (2%)1 (2%)
      Ulcer bleeding1 (2%)1 (2%)
      Hypothyroidism1 (2%)
      Hypophysitis1 (2%)1 (2%)
      Fever2 (3%)
      Dysphonia1 (2%)
      Abbreviations: AV, atrioventricular; ICI-1, first line of ICI treatment; ICI-2, second line of ICI treatment.
      No grade 5 treatment-related adverse events were recorded.
      ∗∗ No grade 4 or 5 treatment-related adverse events were recorded.

      Discussion

      In this international, retrospective, multicenter study an ORR of 26% and a DCR of 55% was observed in patients with HCC who received an ICI-based regimen after prior exposure to ICIs. ICI rechallenge was safe, even in patients who experienced high-grade TRAEs or required corticosteroids at ICI-1.
      Several conclusions can be derived from our study. Firstly, the fact that we had to screen 994 patients in order to include 58 eligible patients (6%) suggests that ICI rechallenge is currently an uncommon practice in HCC, likely because of lacking evidence and approval. However, there is a scientific rationale supporting the use of ICI-based therapies, particularly combinatorial regimens, in patients with primary or acquired resistance to a prior ICI regimen. For instance, upgrading from ICI monotherapy to combination treatment (i.e., dual ICI treatment or ICI plus TKIs/anti-VEGF) or using a different combination than the previous ICI regimen may restore immunotherapy efficacy by synergistically modulating the immunosuppressive tumor immune microenvironment through different mechanisms
      • Shigeta K.
      • Matsui A.
      • Kikuchi H.
      • Klein S.
      • Mamessier E.
      • Chen I.X.
      • et al.
      Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma.
      • Kimura T.
      • Kato Y.
      • Ozawa Y.
      • Kodama K.
      • Ito J.
      • Ichikawa K.
      • et al.
      Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model.
      • Wei S.C.
      • Levine J.H.
      • Cogdill A.P.
      • Zhao Y.
      • Anang N.A.S.
      • Andrews M.C.
      • et al.
      Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade.
      . This may also be achieved by only switching the combination partner (i.e., TKI/anti-VEGF) while continuing with the same ICI. Indeed, in our cohort, most patients (93%) received combination therapies at ICI-2.
      Secondly, patients may benefit from a second ICI regimen, even those with PD as BOR at ICI-1. In fact, ORR was similar at ICI-1 and ICI-2 in our cohort (22% vs. 26%), and comparable to ORRs reported for ICI-based combinations in phase III first-line trials
      • Finn R.S.
      • Qin S.
      • Ikeda M.
      • Galle P.R.
      • Ducreux M.
      • Kim T.Y.
      • et al.
      Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.
      ,

      Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evidence.0(0):EVIDoa2100070.

      . Notably, we observed responses in both patients who received ICI monotherapy and combination therapies at ICI-2, as well as in patients with primary resistance (progression as BOR) at ICI-1.
      A small retrospective study reported acceptable toxicity and an ORR of 16% for dual ICI treatment (anti-CTLA-4 plus anti-PD1) in 25 HCC patients who progressed on prior ICIs
      • Wong J.S.L.
      • Kwok G.G.W.
      • Tang V.
      • Li B.C.W.
      • Leung R.
      • Chiu J.
      • et al.
      Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors.
      . However, in contrast to our cohort, most patients (84%) received prior PD-1 monotherapy, and only 1 patient was treated with atezolizumab/bevacizumab
      • Wong J.S.L.
      • Kwok G.G.W.
      • Tang V.
      • Li B.C.W.
      • Leung R.
      • Chiu J.
      • et al.
      Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors.
      , the standard of care in systemic front-line treatment
      • Gordan J.D.
      • Kennedy E.B.
      • Abou-Alfa G.K.
      • Beg M.S.
      • Brower S.T.
      • Gade T.P.
      • et al.
      Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline.
      . In our cohort, 17 patients received atezolizumab/bevacizumab at ICI-1 and ORR and DCR at ICI-2 in this clinically most relevant subgroup were 18% and 53%, respectively. Atezolizumab/bevacizumab also led to a treatment benefit when given at ICI-2 (ORR, 24%; DCR, 52%).
      Thirdly, the safety profile of the second ICI regimen was good, even in patients who experienced high grade adverse events or required corticosteroids at ICI-1. This is in line with current recommendations suggesting that ICIs may be reinitiated – depending on the severity and site affected – once the adverse event has resolved with or without immunosuppressive treatment
      • Sangro B.
      • Chan S.L.
      • Meyer T.
      • Reig M.
      • El-Khoueiry A.
      • Galle P.R.
      Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma.
      .
      Limitations of our study include the limited sample size, heterogenous population, retrospective nature, and lack of blinded response assessment at predefined intervals. Some patients received multiple lines of systemic therapy which may have led to selection of patients with less aggressive tumors and well-preserved liver function. However, the selection of a better trial population (i.e., better performance status, compensated liver disease) is a conditio sine qua non when investigating later line treatments, and concerns not only our analysis but also large prospective studies testing second- or third-line therapies in HCC. Only patients who are alive with good performance status and well-preserved liver function are eligible for inclusion, while those with deteriorating performance status/liver function would not qualify
      • Llovet J.M.
      • Villanueva A.
      • Marrero J.A.
      • Schwartz M.
      • Meyer T.
      • Galle P.R.
      • et al.
      Trial Design and Endpoints in Hepatocellular Carcinoma: AASLD Consensus Conference.
      .
      In conclusion, our results demonstrate that the use of ICI-based regimens after prior immunotherapy is feasibly and safe, and can lead to a treatment benefit (response and stabilization) in a clinically relevant proportion of patients with HCC. These data provide a rationale for testing ICI-based therapies in patients who progressed on first-line immunotherapy in large prospective trials.

      Appendix A. Supplementary data

      The following is/are the supplementary data to this article:

      References

        • Sung H.
        • Ferlay J.
        • Siegel R.L.
        • Laversanne M.
        • Soerjomataram I.
        • Jemal A.
        • et al.
        Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.
        CA Cancer J Clin. 2021; 71: 209-249
        • Bruix J.
        • Chan S.L.
        • Galle P.R.
        • Rimassa L.
        • Sangro B.
        Systemic treatment of hepatocellular carcinoma: An EASL position paper.
        J Hepatol. 2021; 75: 960-974
        • Pinter M.
        • Jain R.K.
        • Duda D.G.
        The Current Landscape of Immune Checkpoint Blockade in Hepatocellular Carcinoma: A Review.
        JAMA Oncol. 2021; 7: 113-123
        • Finn R.S.
        • Qin S.
        • Ikeda M.
        • Galle P.R.
        • Ducreux M.
        • Kim T.Y.
        • et al.
        Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.
        N Engl J Med. 2020; 382: 1894-1905
        • Gordan J.D.
        • Kennedy E.B.
        • Abou-Alfa G.K.
        • Beg M.S.
        • Brower S.T.
        • Gade T.P.
        • et al.
        Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline.
        J Clin Oncol. 2020; 38: 4317-4345
      1. Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evidence.0(0):EVIDoa2100070.

        • Reig M.
        • Forner A.
        • Rimola J.
        • Ferrer-Fabrega J.
        • Burrel M.
        • Garcia-Criado A.
        • et al.
        BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update.
        J Hepatol. 2022; 76: 681-693
        • Kirstein M.M.
        • Scheiner B.
        • Marwede T.
        • Wolf C.
        • Voigtländer T.
        • Semmler G.
        • et al.
        Sequential systemic treatment in patients with hepatocellular carcinoma.
        Alimentary Pharmacology & Therapeutics. 2020; 52: 205-212
        • Ribas A.
        • Puzanov I.
        • Dummer R.
        • Schadendorf D.
        • Hamid O.
        • Robert C.
        • et al.
        Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.
        Lancet Oncol. 2015; 16: 908-918
        • Ravi P.
        • Mantia C.
        • Su C.
        • Sorenson K.
        • Elhag D.
        • Rathi N.
        • et al.
        Evaluation of the Safety and Efficacy of Immunotherapy Rechallenge in Patients With Renal Cell Carcinoma.
        JAMA Oncol. 2020; 6: 1606-1610
        • Gul A.
        • Stewart T.F.
        • Mantia C.M.
        • Shah N.J.
        • Gatof E.S.
        • Long Y.
        • et al.
        Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors.
        J Clin Oncol. 2020; 38: 3088-3094
        • Shigeta K.
        • Matsui A.
        • Kikuchi H.
        • Klein S.
        • Mamessier E.
        • Chen I.X.
        • et al.
        Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma.
        J Immunother Cancer. 2020; 8
        • Kimura T.
        • Kato Y.
        • Ozawa Y.
        • Kodama K.
        • Ito J.
        • Ichikawa K.
        • et al.
        Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model.
        Cancer Sci. 2018; 109: 3993-4002
        • Wei S.C.
        • Levine J.H.
        • Cogdill A.P.
        • Zhao Y.
        • Anang N.A.S.
        • Andrews M.C.
        • et al.
        Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade.
        Cell. 2017; 170: 1120-1133 e17
        • Wong J.S.L.
        • Kwok G.G.W.
        • Tang V.
        • Li B.C.W.
        • Leung R.
        • Chiu J.
        • et al.
        Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors.
        J Immunother Cancer. 2021; 9
        • Sangro B.
        • Chan S.L.
        • Meyer T.
        • Reig M.
        • El-Khoueiry A.
        • Galle P.R.
        Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma.
        J Hepatol. 2020; 72: 320-341
        • Llovet J.M.
        • Villanueva A.
        • Marrero J.A.
        • Schwartz M.
        • Meyer T.
        • Galle P.R.
        • et al.
        Trial Design and Endpoints in Hepatocellular Carcinoma: AASLD Consensus Conference.
        Hepatology. 2021; 73: 158-191