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Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried ou...

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Autores principales: Dyhl-Polk, Anne, Mikkelsen, Marta Kramer, Ladekarl, Morten, Nielsen, Dorte Lisbet
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234948/
https://www.ncbi.nlm.nih.gov/pubmed/34208788
http://dx.doi.org/10.3390/jcm10122662
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author Dyhl-Polk, Anne
Mikkelsen, Marta Kramer
Ladekarl, Morten
Nielsen, Dorte Lisbet
author_facet Dyhl-Polk, Anne
Mikkelsen, Marta Kramer
Ladekarl, Morten
Nielsen, Dorte Lisbet
author_sort Dyhl-Polk, Anne
collection PubMed
description Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. The search was updated 5 March 2021. We evaluated studies with monotherapy CPI’s, combinations of CPI’s and combinations of CPI’s with other treatment modalities separately. Only studies with at least 10 included patients were considered. Results: We identified 2649 records published in the English language literature. After review, 29 studies remained, including 12 studies with preliminary data only. The obtained overall response rate of PD-1/PDL-1 monotherapy in phase II studies in the second-line setting was 15–20% with disease control in approximately 60% of patients. The responses were of long duration in a subset of patients. Furthermore, the safety profiles were manageable. However, a phase III study comparing nivolumab with sorafenib in the first-line setting and a phase III study evaluating pembrolizumab versus best supportive care in the second-line setting did not meet their prespecified endpoints. More recently, a phase I/II study of nivolumab and ipilimumab has resulted in a response rate of approximately 30% with a median OS of 22 months in the second-line setting. Multiple trials have been initiated to evaluate CPIs in combination with molecularly targeted drugs, especially anti-angiogenic drugs or local therapy. A phase III study investigating atezolizumab plus bevacizumab versus sorafenib in the first-line setting showed significantly increased survival in the combination arm. Conclusions: The combination of atezolizumab and bevacizumab represents a new standard of care in the first-line setting for fit patients with preserved liver function. CPIs can produce durable tumor remission and induce long-standing anti-tumor immunity in a subgroup of patients with advanced HCC. Although phase III trials of CPI monotherapy have been negative, the combination of PD-1/PD-L1 inhibitors with other anti-angiogenic drugs, CTLA-4 inhibitors or other modalities may result in new treatment options for patients with HCC. Research on predictive biomarkers is crucial for further development of CPIs in HCC.
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spelling pubmed-82349482021-06-27 Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Dyhl-Polk, Anne Mikkelsen, Marta Kramer Ladekarl, Morten Nielsen, Dorte Lisbet J Clin Med Review Introduction: Several immune checkpoint inhibitors (CPIs) are under clinical development in hepatocellular carcinoma (HCC) and the field is advancing rapidly. In this comprehensive review, we discuss published results and report on ongoing clinical trials. Methods: A literature search was carried out using PubMed and EMBASE; data reported at international meetings and clinicaltrials.gov were included as well. The search was updated 5 March 2021. We evaluated studies with monotherapy CPI’s, combinations of CPI’s and combinations of CPI’s with other treatment modalities separately. Only studies with at least 10 included patients were considered. Results: We identified 2649 records published in the English language literature. After review, 29 studies remained, including 12 studies with preliminary data only. The obtained overall response rate of PD-1/PDL-1 monotherapy in phase II studies in the second-line setting was 15–20% with disease control in approximately 60% of patients. The responses were of long duration in a subset of patients. Furthermore, the safety profiles were manageable. However, a phase III study comparing nivolumab with sorafenib in the first-line setting and a phase III study evaluating pembrolizumab versus best supportive care in the second-line setting did not meet their prespecified endpoints. More recently, a phase I/II study of nivolumab and ipilimumab has resulted in a response rate of approximately 30% with a median OS of 22 months in the second-line setting. Multiple trials have been initiated to evaluate CPIs in combination with molecularly targeted drugs, especially anti-angiogenic drugs or local therapy. A phase III study investigating atezolizumab plus bevacizumab versus sorafenib in the first-line setting showed significantly increased survival in the combination arm. Conclusions: The combination of atezolizumab and bevacizumab represents a new standard of care in the first-line setting for fit patients with preserved liver function. CPIs can produce durable tumor remission and induce long-standing anti-tumor immunity in a subgroup of patients with advanced HCC. Although phase III trials of CPI monotherapy have been negative, the combination of PD-1/PD-L1 inhibitors with other anti-angiogenic drugs, CTLA-4 inhibitors or other modalities may result in new treatment options for patients with HCC. Research on predictive biomarkers is crucial for further development of CPIs in HCC. MDPI 2021-06-16 /pmc/articles/PMC8234948/ /pubmed/34208788 http://dx.doi.org/10.3390/jcm10122662 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Dyhl-Polk, Anne
Mikkelsen, Marta Kramer
Ladekarl, Morten
Nielsen, Dorte Lisbet
Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma
title Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma
title_full Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma
title_fullStr Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma
title_full_unstemmed Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma
title_short Clinical Trials of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma
title_sort clinical trials of immune checkpoint inhibitors in hepatocellular carcinoma
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234948/
https://www.ncbi.nlm.nih.gov/pubmed/34208788
http://dx.doi.org/10.3390/jcm10122662
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