TY - JOUR
T1 - Immunotherapies for hepatocellular carcinoma
AU - Llovet, Josep M.
AU - Castet, Florian
AU - Heikenwalder, Mathias
AU - Maini, Mala K.
AU - Mazzaferro, Vincenzo
AU - Pinato, David J.
AU - Pikarsky, Eli
AU - Zhu, Andrew X.
AU - Finn, Richard S.
N1 - Publisher Copyright:
© 2021, Springer Nature Limited.
PY - 2022/3
Y1 - 2022/3
N2 - Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.
AB - Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.
KW - Carcinoma, Hepatocellular/drug therapy
KW - Humans
KW - Immune Checkpoint Inhibitors/therapeutic use
KW - Immunotherapy
KW - Liver Neoplasms/drug therapy
KW - Sorafenib/therapeutic use
KW - Tumor Microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85118866220&partnerID=8YFLogxK
U2 - 10.1038/s41571-021-00573-2
DO - 10.1038/s41571-021-00573-2
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C2 - 34764464
AN - SCOPUS:85118866220
SN - 1759-4774
VL - 19
SP - 151
EP - 172
JO - Nature Reviews Clinical Oncology
JF - Nature Reviews Clinical Oncology
IS - 3
ER -