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  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

    Deputy Editor

    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
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    All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
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The Position of Multikinase Inhibitors in the Era of Immune-Checkpoint Inhibitors for Hepatocellular Carcinoma

Beom Kyung Kim1,2,3

1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; 2Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea; 3Yonsei Liver Center, Severance Hospital, Seoul, Korea

Correspondence to: Beom Kyung Kim
ORCID https://orcid.org/0000-0002-5363-2496
E-mail beomkkim@yuhs.ac

See “Sorafenib for 9,923 Patients with Hepatocellular Carcinoma: An Analysis from National Health Insurance Claim Data in South Korea” by Sojung Han, et al. on page 116, Vol. 18, No. 1, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2024;18(1):3-4. https://doi.org/10.5009/gnl230505

Published online January 15, 2024, Published date January 15, 2024

Copyright © Gut and Liver.

Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent cancer globally and is the fourth leading cause of cancer-related mortality. Initially, for approximately a decade, sorafenib, an established multikinase inhibitor, stood as the sole standard therapy demonstrating a proven survival benefit over a placebo in the first-line treatment of advanced-stage HCC. However, the emergence of a novel regimen i.e. lenvatinib as another type of multikinase inhibitor, provided an alternative first-line option compared to sorafenib.1 And then, the introduction of immune-checkpoint inhibitors in the first-line setting for advanced-stage HCC has clearly become the breakthrough in the treatment landscape. The pivotal IMBrave150 trial was the first study to reveal that combining immune-checkpoint inhibitor and anti-vascular endothelial growth factor monoclonal antibodies, specifically atezolizumab plus bevacizumab regimen (Ate/Bev), resulted in an unprecedentedly high objective response rate (29.8% vs 11.3%) and overall survival (19.2 months vs 13.4 months) compared to sorafenib.2-4 Hence, presently, international guidelines recommend Ate/Bev regimen as a 1st-line option.2-4 This paradigm shift has prompted a re-evaluation of the position of multikinase inhibitors like sorafenib in managing advanced-stage HCC.1,4

In this issue of Gut and liver, Han et al.5 performed a comprehensive analysis of real-life data, titled “Sorafenib for 9,923 patients with hepatocellular carcinoma: an analysis from National Health Insurance Claim Data in South Korea,” which revealed that the treatment efficacies of sorafenib aligns with the outcomes observed in previous clinical trials. Their findings also suggest that employing appropriate subsequent therapies after sorafenib should potentially extend patient survival. This retrospective cohort study included all patients receiving sorafenib between July 1, 2008, and December 31, 2014, in the Republic of Korea. Notably, this study is unique as it is the first and only one which demonstrated real-world practices with sorafenib in HCC patients based on so called “big data” from the Korean National Health Insurance, covering around 99% of the population in the Republic of Korea. In particular, the choice of post-sorafenib treatment is crucial for determining patient survival. In one Italian study,6 post-sorafenib survival was independently affected by performance status, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and the reason for discontinuation. So, assuming preserved liver function and acceptable performance status, subsequent treatments following sorafenib could enhance patient survival. In line with this notion, the median overall survival for patients (n=2,591) undergoing post-sorafenib treatment was 14.5 months, significantly longer compared to the 4.6 months observed in patients (n=7,332) receiving only supportive care in the study by Han et al.5 Remarkably, the longest median overall survival of 22.8 months was noted in 90 patients undergoing trans-arterial chemoembolization, followed by radiation therapy and even subsequent conventional cytotoxic chemotherapy. These results are particularly noteworthy, given that regorafenib, a treatment option with proven survival benefits in the context of progression after sorafenib, was not available in the Republic of Korea during the study period from July 2008 to December 2014. Overall, these findings underscore the importance of establishing robust subsequent treatments for eligible patients, taking into consideration their performance status and liver function.

However, with the recommendation of Ate/Bev regimen as the first-line treatment for advanced-stage HCC, there exists a knowledge gap concerning the selection of a second-line regimen following disease progression.7 This gap arises due to a lack of high-level evidence guiding the optimal choice and sequence of management. Up to the present time, most trials demonstrating positive results for second-line regimens have been conducted in the post-sorafenib setting. This is primarily because sorafenib remained the sole option and the "standard of care" for approximately a decade. As more than half of patients treated with Ate/Bev regimen unfortunately experience disease progression during their final disease course, the need for subsequent studies to identify second-line regimens in the near future should be underscored.

Considering the current landscape of immune-checkpoint inhibitors for advanced-stage HCC, it is imperative to reassess the position of multikinase inhibitors like sorafenib or lenvatinib.8 Firstly, Yoo et al.9 conducted a multinational, multicenter retrospective cohort study to examine the clinical outcomes of multikinase inhibitors as a second-line regimen following progression on Ate/Bev regimen. Among 49 patients in the study, 59.2% utilized sorafenib, 38.8% used lenvatinib, and 1% used cabozantinib as subsequent therapy. The results showed a median progression-free survival of 3.4 months (95% confidence interval, 1.8 to 4.9) and an overall survival of 14.7 months (95% confidence interval, 8.1 to 21.2). Secondly, the combination of multikinase inhibitors with immune-checkpoint inhibitors emerges as a potential option. In a study with a limited sample size, the use of nivolumab plus sorafenib demonstrated improved overall survival compared to sorafenib alone.10 Likewise, there had been similar kinds of clinical trials based upon lenvatinib.1 To determine optimal solutions for advanced-stage HCC, it is also essential to assess the efficacy and safety of various combinations based upon multikinase inhibitors plus immune-checkpoint inhibitors.

In conclusion, there is a crucial need to reassess the position of multikinase inhibitors in the context of managing advanced-stage HCC in the era of immune-checkpoint inhibitors. Given the current lack of a well-established second-line regimen following disease progression on Ate/Bev regimen, the utilization of multikinase inhibitors, either alone or in combination with other modalities such as immune-checkpoint inhibitors or loco-regional treatments, holds promise for potentially extending both patient survival and improving their quality of life.

No potential conflict of interest relevant to this article was reported.

  1. Lee MMP, Chan LL, Chan SL. The role of lenvatinib in the era of immunotherapy of hepatocellular carcinoma. J Liver Cancer 2023;23:262-271.
    Pubmed KoreaMed CrossRef
  2. National Comprehensive Cancer Network (NCCN). Guidelines [Internet]. Plymouth Meeting: NCCN; c2023 [cited 28 December 2023].
    Available from: https://www.nccn.org/
  3. Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022;28:583-705.
    Pubmed KoreaMed CrossRef
  4. Bruix J, Chan SL, Galle PR, Rimassa L, Sangro B. Systemic treatment of hepatocellular carcinoma: An EASL position paper. J Hepatol 2021;75:960-974.
    Pubmed CrossRef
  5. Han S, Kim DY, Lim HY, et al. Sorafenib for 9,923 patients with hepatocellular carcinoma: an analysis from National Health Insurance Claim Data in South Korea. Gut Liver 2024;18:116-124.
    Pubmed CrossRef
  6. Iavarone M, Cabibbo G, Biolato M, et al. Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib. Hepatology 2015;62:784-791.
    Pubmed CrossRef
  7. Goh MJ, Sinn DH, Kim JM, et al. Clinical practice guideline and real-life practice in hepatocellular carcinoma: a Korean perspective. Clin Mol Hepatol 2023;29:197-205.
    Pubmed KoreaMed CrossRef
  8. Chan LL, Chan SL. The evolving role of lenvatinib at the new era of first-line hepatocellular carcinoma treatment. Clin Mol Hepatol 2023;29:909-923.
    Pubmed KoreaMed CrossRef
  9. Yoo C, Kim JH, Ryu MH, et al. Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: a multinational multicenter retrospective study. Liver Cancer 2021;10:107-114.
    Pubmed KoreaMed CrossRef
  10. Peng TR, Wu CC, Chang SY, Chen YC, Wu TW, Hsu CS. Therapeutic efficacy of nivolumab plus sorafenib therapy in patients with unresectable hepatocellular carcinoma. Int Immunopharmacol 2022;112:109223.
    Pubmed CrossRef

Article

Editorial

Gut and Liver 2024; 18(1): 3-4

Published online January 15, 2024 https://doi.org/10.5009/gnl230505

Copyright © Gut and Liver.

The Position of Multikinase Inhibitors in the Era of Immune-Checkpoint Inhibitors for Hepatocellular Carcinoma

Beom Kyung Kim1,2,3

1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea; 2Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea; 3Yonsei Liver Center, Severance Hospital, Seoul, Korea

Correspondence to:Beom Kyung Kim
ORCID https://orcid.org/0000-0002-5363-2496
E-mail beomkkim@yuhs.ac

See “Sorafenib for 9,923 Patients with Hepatocellular Carcinoma: An Analysis from National Health Insurance Claim Data in South Korea” by Sojung Han, et al. on page 116, Vol. 18, No. 1, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body

Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent cancer globally and is the fourth leading cause of cancer-related mortality. Initially, for approximately a decade, sorafenib, an established multikinase inhibitor, stood as the sole standard therapy demonstrating a proven survival benefit over a placebo in the first-line treatment of advanced-stage HCC. However, the emergence of a novel regimen i.e. lenvatinib as another type of multikinase inhibitor, provided an alternative first-line option compared to sorafenib.1 And then, the introduction of immune-checkpoint inhibitors in the first-line setting for advanced-stage HCC has clearly become the breakthrough in the treatment landscape. The pivotal IMBrave150 trial was the first study to reveal that combining immune-checkpoint inhibitor and anti-vascular endothelial growth factor monoclonal antibodies, specifically atezolizumab plus bevacizumab regimen (Ate/Bev), resulted in an unprecedentedly high objective response rate (29.8% vs 11.3%) and overall survival (19.2 months vs 13.4 months) compared to sorafenib.2-4 Hence, presently, international guidelines recommend Ate/Bev regimen as a 1st-line option.2-4 This paradigm shift has prompted a re-evaluation of the position of multikinase inhibitors like sorafenib in managing advanced-stage HCC.1,4

In this issue of Gut and liver, Han et al.5 performed a comprehensive analysis of real-life data, titled “Sorafenib for 9,923 patients with hepatocellular carcinoma: an analysis from National Health Insurance Claim Data in South Korea,” which revealed that the treatment efficacies of sorafenib aligns with the outcomes observed in previous clinical trials. Their findings also suggest that employing appropriate subsequent therapies after sorafenib should potentially extend patient survival. This retrospective cohort study included all patients receiving sorafenib between July 1, 2008, and December 31, 2014, in the Republic of Korea. Notably, this study is unique as it is the first and only one which demonstrated real-world practices with sorafenib in HCC patients based on so called “big data” from the Korean National Health Insurance, covering around 99% of the population in the Republic of Korea. In particular, the choice of post-sorafenib treatment is crucial for determining patient survival. In one Italian study,6 post-sorafenib survival was independently affected by performance status, prothrombin time, extrahepatic tumor spread, macrovascular invasion, and the reason for discontinuation. So, assuming preserved liver function and acceptable performance status, subsequent treatments following sorafenib could enhance patient survival. In line with this notion, the median overall survival for patients (n=2,591) undergoing post-sorafenib treatment was 14.5 months, significantly longer compared to the 4.6 months observed in patients (n=7,332) receiving only supportive care in the study by Han et al.5 Remarkably, the longest median overall survival of 22.8 months was noted in 90 patients undergoing trans-arterial chemoembolization, followed by radiation therapy and even subsequent conventional cytotoxic chemotherapy. These results are particularly noteworthy, given that regorafenib, a treatment option with proven survival benefits in the context of progression after sorafenib, was not available in the Republic of Korea during the study period from July 2008 to December 2014. Overall, these findings underscore the importance of establishing robust subsequent treatments for eligible patients, taking into consideration their performance status and liver function.

However, with the recommendation of Ate/Bev regimen as the first-line treatment for advanced-stage HCC, there exists a knowledge gap concerning the selection of a second-line regimen following disease progression.7 This gap arises due to a lack of high-level evidence guiding the optimal choice and sequence of management. Up to the present time, most trials demonstrating positive results for second-line regimens have been conducted in the post-sorafenib setting. This is primarily because sorafenib remained the sole option and the "standard of care" for approximately a decade. As more than half of patients treated with Ate/Bev regimen unfortunately experience disease progression during their final disease course, the need for subsequent studies to identify second-line regimens in the near future should be underscored.

Considering the current landscape of immune-checkpoint inhibitors for advanced-stage HCC, it is imperative to reassess the position of multikinase inhibitors like sorafenib or lenvatinib.8 Firstly, Yoo et al.9 conducted a multinational, multicenter retrospective cohort study to examine the clinical outcomes of multikinase inhibitors as a second-line regimen following progression on Ate/Bev regimen. Among 49 patients in the study, 59.2% utilized sorafenib, 38.8% used lenvatinib, and 1% used cabozantinib as subsequent therapy. The results showed a median progression-free survival of 3.4 months (95% confidence interval, 1.8 to 4.9) and an overall survival of 14.7 months (95% confidence interval, 8.1 to 21.2). Secondly, the combination of multikinase inhibitors with immune-checkpoint inhibitors emerges as a potential option. In a study with a limited sample size, the use of nivolumab plus sorafenib demonstrated improved overall survival compared to sorafenib alone.10 Likewise, there had been similar kinds of clinical trials based upon lenvatinib.1 To determine optimal solutions for advanced-stage HCC, it is also essential to assess the efficacy and safety of various combinations based upon multikinase inhibitors plus immune-checkpoint inhibitors.

In conclusion, there is a crucial need to reassess the position of multikinase inhibitors in the context of managing advanced-stage HCC in the era of immune-checkpoint inhibitors. Given the current lack of a well-established second-line regimen following disease progression on Ate/Bev regimen, the utilization of multikinase inhibitors, either alone or in combination with other modalities such as immune-checkpoint inhibitors or loco-regional treatments, holds promise for potentially extending both patient survival and improving their quality of life.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

References

  1. Lee MMP, Chan LL, Chan SL. The role of lenvatinib in the era of immunotherapy of hepatocellular carcinoma. J Liver Cancer 2023;23:262-271.
    Pubmed KoreaMed CrossRef
  2. National Comprehensive Cancer Network (NCCN). Guidelines [Internet]. Plymouth Meeting: NCCN; c2023 [cited 28 December 2023]. Available from: https://www.nccn.org/
  3. Korean Liver Cancer Association (KLCA) and National Cancer Center (NCC) Korea. 2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma. Clin Mol Hepatol 2022;28:583-705.
    Pubmed KoreaMed CrossRef
  4. Bruix J, Chan SL, Galle PR, Rimassa L, Sangro B. Systemic treatment of hepatocellular carcinoma: An EASL position paper. J Hepatol 2021;75:960-974.
    Pubmed CrossRef
  5. Han S, Kim DY, Lim HY, et al. Sorafenib for 9,923 patients with hepatocellular carcinoma: an analysis from National Health Insurance Claim Data in South Korea. Gut Liver 2024;18:116-124.
    Pubmed CrossRef
  6. Iavarone M, Cabibbo G, Biolato M, et al. Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib. Hepatology 2015;62:784-791.
    Pubmed CrossRef
  7. Goh MJ, Sinn DH, Kim JM, et al. Clinical practice guideline and real-life practice in hepatocellular carcinoma: a Korean perspective. Clin Mol Hepatol 2023;29:197-205.
    Pubmed KoreaMed CrossRef
  8. Chan LL, Chan SL. The evolving role of lenvatinib at the new era of first-line hepatocellular carcinoma treatment. Clin Mol Hepatol 2023;29:909-923.
    Pubmed KoreaMed CrossRef
  9. Yoo C, Kim JH, Ryu MH, et al. Clinical outcomes with multikinase inhibitors after progression on first-line atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: a multinational multicenter retrospective study. Liver Cancer 2021;10:107-114.
    Pubmed KoreaMed CrossRef
  10. Peng TR, Wu CC, Chang SY, Chen YC, Wu TW, Hsu CS. Therapeutic efficacy of nivolumab plus sorafenib therapy in patients with unresectable hepatocellular carcinoma. Int Immunopharmacol 2022;112:109223.
    Pubmed CrossRef
Gut and Liver

Vol.18 No.1
January, 2024

pISSN 1976-2283
eISSN 2005-1212

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