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Krupa K, Fudalej M, Cencelewicz-Lesikow A, Badowska-Kozakiewicz A, Czerw A, Deptała A. Current Treatment Methods in Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:4059. [PMID: 39682245 DOI: 10.3390/cancers16234059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent malignant tumour worldwide. Depending on the stage of the tumour and liver function, a variety of treatment options are indicated. Traditional radiotherapy and chemotherapy are ineffective against HCC; however, the U.S. Food and Drug Administration (FDA) has approved radiofrequency ablation (RFA), surgical resection, and transarterial chemoembolization (TACE) for advanced HCC. On the other hand, liver transplantation is recommended in the early stages of the disease. Tyrosine kinase inhibitors (TKIs) like lenvatinib and sorafenib, immunotherapy and anti-angiogenesis therapy, including pembrolizumab, bevacizumab, tremelimumab, durvalumab, camrelizumab, and atezolizumab, are other treatment options for advanced HCC. Moreover, to maximize outcomes for patients with HCC, the combination of immune checkpoint inhibitors (ICIs) along with targeted therapies or local ablative therapy is being investigated. This review elaborates on the current status of HCC treatment, outlining the most recent clinical study results and novel approaches.
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Affiliation(s)
- Kamila Krupa
- Students' Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Marta Fudalej
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
- Department of Oncology, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | - Anna Cencelewicz-Lesikow
- Department of Oncology, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | | | - Aleksandra Czerw
- Department of Health Economics and Medical Law, Medical University of Warsaw, 01-445 Warsaw, Poland
- Department of Economic and System Analyses, National Institute of Public Health NIH-National Research Institute, 00-791 Warsaw, Poland
| | - Andrzej Deptała
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
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Xiong J, Ouyang W, Yang M, Gao Z, Zhou H, Lou H, Guo Y, Xu Z, Zheng L, Liu Y, Wang Z, Sun P, Niyazi H, Wang J, Chen Y, Zhang B, Li L, Kang X, Guo W. Efficacy and Safety of Iparomlimab, an Anti-PD-1 Antibody, in Patients with Advanced Solid Tumors: A Phase 1c Study. Adv Ther 2024; 41:4153-4171. [PMID: 39276185 DOI: 10.1007/s12325-024-02981-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 08/22/2024] [Indexed: 09/16/2024]
Abstract
INTRODUCTION Iparomlimab (QL1604) is a humanized immunoglobulin G4 mAb against programmed cell death protein 1 (PD-1). Here, we report the preliminary efficacy, safety, pharmacokinetics, and immunogenicity of iparomlimab in patients with advanced solid tumors. METHODS In this open-label, phase 1c study, patients with advanced or metastatic solid tumors, either failed or had no standard therapies available, were enrolled and received intravenous iparomlimab at 3 mg/kg once every 3 weeks. The primary efficacy endpoint was the objective response rate (ORR) assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS Between July 20, 2020, and September 6, 2021, 71 patients were enrolled and received at least one dose of iparomlimab. The ORR was 9.9% (7/71) and disease control rate was 36.6% (26/71). Median duration of response of all responders was 10.7 months [95% confidence interval (CI), 1.4-not estimable]. Additionally, the median time to progression, progression-free survival, and overall survival were 1.4 months (95% CI, 1.4-2.8), 1.4 months (95% CI, 1.4-2.7), and 9.7 months (95% CI, 7.2-15.3), respectively. A total of 52 (73.2%) patients experienced treatment-related adverse events (TRAEs) (grade ≥ 3, 19.7%). The most common TRAE (≥ 10%) was anemia (18.3%). A total of 20 (28.2%) experienced immune-related adverse events (grade ≥ 3, 7.0%). TRAEs leading to discontinuation of study drug occurred in 4 (5.6%) patients, including immune-mediated myocarditis (2 patients), Guillain-Barré syndrome (1 patient), and diarrhea (1 patient). CONCLUSIONS Iparomlimab showed preliminary clinical activity and had a manageable safety profile in patients with advanced solid tumors. These results support further investigation of iparomlimab as monotherapy or in combination therapy in advanced solid tumors. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT05801094. Retrospectively registered in 2023-03-24.
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Affiliation(s)
- Jianping Xiong
- Department of Medical Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Weiwei Ouyang
- Phase I Ward, Guizhou Cancer Hospital, Guiyang, China
| | - Mengxiang Yang
- Department of Oncology, Liaocheng People's Hospital, Liaocheng, China
| | - Zhenyuan Gao
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Huan Zhou
- Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Hanmei Lou
- Phase I Ward, Zhejiang Cancer Hospital, Hangzhou, China
| | - Yabing Guo
- Liver Cancer Center/Phase I Clinical Research Laboratory, Nanfang Hospital, Guangzhou, China
| | - Zhongyuan Xu
- Liver Cancer Center/Phase I Clinical Research Laboratory, Nanfang Hospital, Guangzhou, China
| | - Ling Zheng
- Phase I Ward, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Ying Liu
- The Third Ward of Digestive Diseases, Henan Cancer Hospital, Zhengzhou, China
| | - Zhongfeng Wang
- Henan Cancer Hospital, The First Hospital of Jilin University, Changchun, China
| | - Ping Sun
- Department of Medical Oncology, Yantai Yuhuangding Hospital, Yantai, China
| | - Huerxidan Niyazi
- Department of Oncology/Phase I Ward, The First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China
| | - Jianhua Wang
- Department of Oncology/Phase I Ward, The First Affiliated Hospital of Xinjiang Medical University, Wulumuqi, China
| | - Yan Chen
- Clinical Research and Development Center, Qilu Pharmaceutical Co., Ltd, Jinan, China
| | - Baihui Zhang
- Clinical Research and Development Center, Qilu Pharmaceutical Co., Ltd, Jinan, China
| | - Lingyan Li
- Clinical Research and Development Center, Qilu Pharmaceutical Co., Ltd, Jinan, China
| | - Xiaoyan Kang
- Clinical Research and Development Center, Qilu Pharmaceutical Co., Ltd, Jinan, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
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3
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Tan BB, Fu Y, Shao MH, Chen HL, Liu P, Fan C, Zhang H. Combined transarterial chemoembolization and tislelizumab for patients with unresectable hepatocellular carcinoma. World J Gastrointest Surg 2024; 16:2829-2841. [PMID: 39351562 PMCID: PMC11438790 DOI: 10.4240/wjgs.v16.i9.2829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 07/11/2024] [Accepted: 08/01/2024] [Indexed: 09/18/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) often presents as unresectable, necessitating effective treatment modalities. Combining transarterial chemoembolization (TACE) with immunotherapy and targeted therapy has shown promise, yet real-world evidence is needed. AIM To investigate effectiveness and safety of TACE with tislelizumab ± targeted therapy for unresectable HCC in real-world setting. METHODS This retrospective study included patients with unresectable HCC receiving combined treatment of TACE and tislelizumab. The clinical outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). All patients were evaluated according to the mRECIST criteria. The adverse event (AE) was also assessed. RESULTS In this study of 56 patients with median follow-up of 10.9 months, 7 had previous immunotherapy. Tislelizumab was administered before TACE in 21 (37.50%) and after in 35 (62.50%) patients, with 91.07% receiving concurrent targeted therapy. Median PFS was 14.0 (95%CI: 7.0-18.00) months, and OS was 28 (95%CI: 2.94-53.05) months. Patients with prior immunotherapy had shorter PFS (6 vs. 18 months, P = 0.006). Overall ORR and DCR were 82.14% and 87.50%. Grade ≥ 3 treatment-related AEs included increased alanine aminotransferase (8.93%), aspartate aminotransferase (10.71%), and total bilirubin (3.57%). CONCLUSION The combination of TACE and tislelizumab, with or without targeted therapy, demonstrated promising efficacy and safety in unresectable HCC, especially in immunotherapy-naive patients, warranting further prospective validation studies.
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Affiliation(s)
- Bin-Bin Tan
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Ying Fu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Third Military Medical University (Army Medical University), Jiangbei Area (The 958th Hospital of Chinese People's Liberation Army), Chongqing 400020, China
| | - Ming-Hua Shao
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hai-Lei Chen
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Ping Liu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Third Military Medical University (Army Medical University), Jiangbei Area (The 958th Hospital of Chinese People's Liberation Army), Chongqing 400020, China
| | - Chao Fan
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Third Military Medical University (Army Medical University), Jiangbei Area (The 958th Hospital of Chinese People's Liberation Army), Chongqing 400020, China
| | - Hui Zhang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing 400038, China
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4
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Liu X, Xia F, Chen Y, Sun H, Yang Z, Chen B, Zhao M, Bi X, Peng T, Ainiwaer A, Luo Z, Wang F, Lu Y, National Clinical Research Center for Infectious Diseases, Society of Hepatology, Beijing Medical Association, Translational Medicine Branch, China Association of Gerontology and Geriatrics. Chinese expert consensus on refined diagnosis, treatment, and management of advanced primary liver cancer (2023 edition). LIVER RESEARCH (BEIJING, CHINA) 2024; 8:61-71. [PMID: 39959878 PMCID: PMC11771258 DOI: 10.1016/j.livres.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/10/2024] [Accepted: 05/13/2024] [Indexed: 11/25/2024]
Abstract
Hepatocellular carcinoma (HCC), commonly known as primary liver cancer, is a major cause of malignant tumors and cancer-related deaths in China, accounting for approximately 85% of all cancer cases in the country. Several guidelines have been used to diagnose and treat liver cancer. However, these guidelines provide a broad definition for classifying advanced liver cancer, with an emphasis on a singular approach, without considering treatment options for individual patients. Therefore, it is necessary to establish a comprehensive and practical expert consensus, specifically for China, to enhance the diagnosis and treatment of HCC using the Delphi method. The classification criteria were refined for Chinese patients with HCC, and the corresponding optimal treatment regimen recommendations were developed. These recommendations took into account various factors, including tumor characteristics, vascular tumor thrombus grade, distant metastasis, liver function status, portal hypertension, and the hepatitis B virus replication status of patients with primary HCC, along with treatment prognosis. The findings and recommendations provide detailed, scientific, and reasonable individualized diagnosis and treatment strategies for clinicians.
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Affiliation(s)
- Xiufeng Liu
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China
| | - Feng Xia
- Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Yue Chen
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Huichuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhengqiang Yang
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Chen
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ming Zhao
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Xinyu Bi
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Aizier Ainiwaer
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Zhiwen Luo
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fusheng Wang
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yinying Lu
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - National Clinical Research Center for Infectious Diseases
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China
- Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Society of Hepatology, Beijing Medical Association
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China
- Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Translational Medicine Branch
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China
- Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - China Association of Gerontology and Geriatrics
- Department of Medical Oncology, Bayi Hospital Affiliated to Nanjing Chinese Medical University, Nanjing, Jiangsu, China
- Department of Hepatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Senior Department of Infectious Diseases, The Fifth Medical Center of PLA General Hospital, Beijing, China
- Comprehensive Liver Cancer Center, The Fifth Medical Center of PLA General Hospital, Beijing, China
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5
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Ali FEM, Ibrahim IM, Althagafy HS, Hassanein EHM. Role of immunotherapies and stem cell therapy in the management of liver cancer: A comprehensive review. Int Immunopharmacol 2024; 132:112011. [PMID: 38581991 DOI: 10.1016/j.intimp.2024.112011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/01/2024] [Accepted: 04/02/2024] [Indexed: 04/08/2024]
Abstract
Liver cancer (LC) is the sixth most common disease and the third most common cause of cancer-related mortality. The WHO predicts that more than 1 million deaths will occur from LC by 2030. Hepatocellular carcinoma (HCC) is a common form of primary LC. Today, the management of LC involves multiple disciplines, and multimodal therapy is typically selected on an individual basis, considering the intricate interactions between the patient's overall health, the stage of the tumor, and the degree of underlying liver disease. Currently, the treatment of cancers, including LC, has undergone a paradigm shift in the last ten years because of immuno-oncology. To treat HCC, immune therapy approaches have been developed to enhance or cause the body's natural immune response to specifically target tumor cells. In this context, immune checkpoint pathway inhibitors, engineered cytokines, adoptive cell therapy, immune cells modified with chimeric antigen receptors, and therapeutic cancer vaccines have advanced to clinical trials and offered new hope to cancer patients. The outcomes of these treatments are encouraging. Additionally, treatment using stem cells is a new approach for restoring deteriorated tissues because of their strong differentiation potential and capacity to release cytokines that encourage cell division and the formation of blood vessels. Although there is no proof that stem cell therapy works for many types of cancer, preclinical research on stem cells has shown promise in treating HCC. This review provides a recent update regarding the impact of immunotherapy and stem cells in HCC and promising outcomes.
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Affiliation(s)
- Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt; Michael Sayegh, Faculty of Pharmacy, Aqaba University of Technology, Aqaba 77110, Jordan.
| | - Islam M Ibrahim
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Hanan S Althagafy
- Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt
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Qin S, Kudo M, Meyer T, Bai Y, Guo Y, Meng Z, Satoh T, Marino D, Assenat E, Li S, Chen Y, Boisserie F, Abdrashitov R, Finn RS, Vogel A, Zhu AX. Tislelizumab vs Sorafenib as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Phase 3 Randomized Clinical Trial. JAMA Oncol 2023; 9:1651-1659. [PMID: 37796513 PMCID: PMC10557031 DOI: 10.1001/jamaoncol.2023.4003] [Citation(s) in RCA: 97] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 06/13/2023] [Indexed: 10/06/2023]
Abstract
Importance Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and additional first-line treatments are needed. The programmed cell death protein 1 inhibitor tislelizumab demonstrated efficacy and a tolerable safety profile as second-line HCC treatment. Objective To investigate efficacy and safety of tislelizumab vs sorafenib tosylate for first-line treatment of unresectable HCC. Design, Setting, and Participants The open-label, global, multiregional phase 3 RATIONALE-301 randomized clinical trial enrolled systemic therapy-naive adults with histologically confirmed HCC, Barcelona Clinic Liver Cancer stage B or C disease, disease progression following (or patient was not amenable to) locoregional therapy, Eastern Cooperative Oncology Group performance status of 1 or less, and Child-Pugh class A, between December 27, 2017, and October 2, 2019. Data cutoff was July 11, 2022. Intervention Patients were randomized 1:1 to receive tislelizumab, 200 mg intravenously every 3 weeks, or sorafenib tosylate, 400 mg orally twice daily. Main Outcomes and Measures The primary end point was overall survival (OS); secondary end points included objective response rate, progression-free survival, duration of response, and safety. Results A total of 674 patients were included in the analysis (570 men [84.6%]; median age, 61 years [range, 23-86 years]). As of July 11, 2022, minimum study follow-up was 33 months. The primary end point of OS noninferiority of tislelizumab vs sorafenib was met in the intention-to-treat population (n = 674); median overall survival was 15.9 (95% CI, 13.2-19.7) months vs 14.1 (95% CI, 12.6-17.4) months, respectively (hazard ratio [HR], 0.85 [95.003% CI, 0.71-1.02]), and superiority of tislelizumab vs sorafenib was not met. The objective response rate was 14.3% (n = 49) for tislelizumab vs 5.4% (n = 18) for sorafenib, and median duration of response was 36.1 (95% CI, 16.8 to not evaluable) months vs 11.0 (95% CI, 6.2-14.7) months, respectively. Median progression-free survival was 2.1 (95% CI, 2.1-3.5) months vs 3.4 (95% CI, 2.2-4.1) months with tislelizumab vs sorafenib (HR, 1.11 [95% CI, 0.92-1.33]). The incidence of treatment-emergent adverse events (AEs) was 96.2% (325 of 338 patients) for tislelizumab and 100% (n = 324) for sorafenib. Grade 3 or greater treatment-related AEs were reported in 75 patients (22.2%) receiving tislelizumab and 173 (53.4%) receiving sorafenib. There was a lower incidence of treatment-related AEs leading to drug discontinuation (21 [6.2%] vs 33 [10.2%]) and drug modification (68 [20.1%] vs 187 [57.7%]) with tislelizumab vs sorafenib. Conclusions and Relevance In RATIONALE-301, tislelizumab demonstrated OS benefit that was noninferior vs sorafenib, with a higher objective response rate and more durable responses, while median progression-free survival was longer with sorafenib. Tislelizumab demonstrated a favorable safety profile vs sorafenib. Trial Registration ClinicalTrials.gov Identifier: NCT03412773.
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Affiliation(s)
- Shukui Qin
- Nanjing Tianyinshang Hospital of China Pharmaceutical University, Nanjing, China
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Tim Meyer
- Academic Department of Oncology, Royal Free Hospital NHS Trust and University College London, London, United Kingdom
| | - Yuxian Bai
- Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yabing Guo
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiqiang Meng
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Osaka, Japan
| | - Donatella Marino
- Department of Oncology, Ordine Mauriziano Hospital, Turin, Italy
| | - Eric Assenat
- Department of Oncology, Montpellier University Hospital, Montpellier, France
| | - Songzi Li
- Biometrics, BeiGene Ltd, Ridgefield Park, New Jersey
| | - Yaxi Chen
- Clinical Science, BeiGene (Beijing) Co, Ltd, Beijing, China
| | | | | | - Richard S. Finn
- Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Andrew X. Zhu
- Jiahui International Cancer Center, Jiahui Health, Shanghai, China
- Massachusetts General Hospital, Harvard Medical School, Boston
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7
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Chami P, Diab Y, Khalil DN, Azhari H, Jarnagin WR, Abou-Alfa GK, Harding JJ, Hajj J, Ma J, El Homsi M, Reyngold M, Crane C, Hajj C. Radiation and Immune Checkpoint Inhibitors: Combination Therapy for Treatment of Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:16773. [PMID: 38069095 PMCID: PMC10706661 DOI: 10.3390/ijms242316773] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/24/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
The liver tumor immune microenvironment has been thought to possess a critical role in the development and progression of hepatocellular carcinoma (HCC). Despite the approval of immune checkpoint inhibitors (ICIs), such as programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) inhibitors, for several types of cancers, including HCC, liver metastases have shown evidence of resistance or poor response to immunotherapies. Radiation therapy (RT) has displayed evidence of immunosuppressive effects through the upregulation of immune checkpoint molecules post-treatment. However, it was revealed that the limitations of ICIs can be overcome through the use of RT, as it can reshape the liver immune microenvironment. Moreover, ICIs are able to overcome the RT-induced inhibitory signals, effectively restoring anti-tumor activity. Owing to the synergetic effect believed to arise from the combination of ICIs with RT, several clinical trials are currently ongoing to assess the efficacy and safety of this treatment for patients with HCC.
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Affiliation(s)
- Perla Chami
- Faculty of Medicine, American University of Beirut, Beirut 1107, Lebanon;
| | - Youssef Diab
- Faculty of Medicine, University of Balamand, Beirut 1100, Lebanon; (Y.D.)
| | - Danny N. Khalil
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | - Hassan Azhari
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | - William R. Jarnagin
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
- Department of Surgery, Weill Medical College, Cornell University, New York, NY 10021, USA
| | - Ghassan K. Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
- Department of Medicine, Weill Medical College, Cornell University, New York, NY 10021, USA
| | - James J. Harding
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
- Department of Medicine, Weill Medical College, Cornell University, New York, NY 10021, USA
| | - Joseph Hajj
- Faculty of Medicine, University of Balamand, Beirut 1100, Lebanon; (Y.D.)
| | - Jennifer Ma
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | - Maria El Homsi
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | - Marsha Reyngold
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
| | | | - Carla Hajj
- Memorial Sloan Kettering Cancer Center, New York, NY 10027, USA
- New York Proton Center, New York, NY 10035, USA
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Qin S, Chen Z, Fang W, Ren Z, Xu R, Ryoo BY, Meng Z, Bai Y, Chen X, Liu X, Xiao J, Ho GF, Mao Y, Wang X, Ying J, Li J, Zhong W, Zhou Y, Siegel AB, Hao C. Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 2023; 41:1434-1443. [PMID: 36455168 PMCID: PMC9995104 DOI: 10.1200/jco.22.00620] [Citation(s) in RCA: 115] [Impact Index Per Article: 57.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 08/26/2022] [Accepted: 10/10/2022] [Indexed: 12/03/2022] Open
Abstract
PURPOSE We evaluated the efficacy and safety of pembrolizumab in patients from Asia with previously treated advanced hepatocellular carcinoma (HCC). METHODS In a double-blind, phase III trial, 453 patients with advanced HCC and progression during or after treatment with or intolerance to sorafenib or oxaliplatin-based chemotherapy were randomly assigned in a 2:1 ratio to receive pembrolizumab (200 mg) or placebo once every 3 weeks for ≤ 35 cycles plus best supportive care. The primary end point was overall survival (one-sided significance threshold, P = .0193 [final analysis]). Secondary end points included progression-free survival (PFS) and objective response rate (ORR; one-sided significance threshold, P = .0134 and .0091, respectively [second interim analysis]; RECIST version 1.1, by blinded independent central review). RESULTS Median overall survival was longer in the pembrolizumab group than in the placebo group (14.6 v 13.0 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P = .0180). Median PFS was also longer in the pembrolizumab group than in the placebo group (2.6 v 2.3 months; hazard ratio for progression or death, 0.74; 95% CI, 0.60 to 0.92; P = .0032). ORR was greater in the pembrolizumab group (12.7% [95% CI, 9.1 to 17.0]) than in the placebo group (1.3% [95% CI, 0.2 to 4.6]; P < .0001). Treatment-related adverse events occurred in 66.9% of patients (grade 3, 12.0%; grade 4, 1.3%; grade 5, 1.0%) in the pembrolizumab group and 49.7% of patients (grade 3, 5.9%; grade 4, 0%; grade 5, 0%) in the placebo group. CONCLUSION In patients from Asia with previously treated advanced HCC, pembrolizumab significantly prolonged overall survival and PFS, and ORR was greater versus placebo.
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Affiliation(s)
- Shukui Qin
- Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, China
| | - Zhendong Chen
- The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Weijia Fang
- The First Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Zhenggang Ren
- Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ruocai Xu
- Hunan Cancer Hospital, Changsha, China
| | - Baek-Yeol Ryoo
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Zhiqiang Meng
- Fudan University Shanghai Cancer Center, Shanghai, China
| | - Yuxian Bai
- Harbin Medical University Cancer Hospital, Harbin, China
| | - Xiaoming Chen
- Guangdong Provincial People's Hospital, Guangzhou, China
- Guangdong Academy of Medical Science, Guangzhou, China
| | - Xiufeng Liu
- Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, China
| | - Juxiang Xiao
- The First Affiliated Hospital of Xi'An Jiaotong University, Xi'an, China
| | - Gwo Fuang Ho
- University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Yimin Mao
- Shanghai Jiaotong University School of Medicine, Renji Hospital, Shanghai, China
| | - Xin Wang
- West China Hospital of Sichuan University, Chengdu, China
| | - Jieer Ying
- Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | | | | | | | | | - Chunyi Hao
- Peking University Cancer Hospital, Beijing, China
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Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2023; 29:1054-1075. [PMID: 36844141 PMCID: PMC9950866 DOI: 10.3748/wjg.v29.i6.1054] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/23/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world’s deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying liver condition. Despite promising preclinical and early-phase clinical trials for some drugs, existing systemic therapeutic methods for advanced tumor stages remain limited, underlining an unmet clinical need. In current years, cancer immunotherapy has made significant progress, opening up new treatment options for HCC. HCC, on the other hand, has a variety of causes and can affects the body’s immune system via a variety of mechanisms. With the speedy advancement of synthetic biology and genetic engineering, a range of innovative immunotherapies, such as immune checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, and anti-PD ligand 1 cell death antibodies], therapeutic cancer vaccines, engineered cytokines, and adoptive cell therapy have all been used for the treatment of advanced HCC. In this review, we summarize the present clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent clinical trial outcomes, and address future perspectives in the field of liver cancer.
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Affiliation(s)
- Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Liu Y, Pan J, Gao F, Xu W, Li H, Qi X. Efficacy and Safety of PD-1/PD-L1 Inhibitors in Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-analysis. Adv Ther 2023; 40:521-549. [PMID: 36399316 DOI: 10.1007/s12325-022-02371-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/24/2022] [Indexed: 11/20/2022]
Abstract
INTRODUCTION Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly employed for the treatment of various cancers in clinical practice. This study aimed to systematically evaluate the efficacy and safety of PD-1/PD-L1 inhibitors for advanced hepatocellular carcinoma (HCC). METHODS PubMed, EMBASE, Cochrane library, Web of Science, and Abstracts of American Society of Clinical Oncology proceedings databases were searched. Objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), median overall survival (OS), and incidence of adverse events (AEs) and drug withdrawal were pooled. Odds ratio (OR) and hazard ratio (HR) were calculated to analyze the difference in the ORR, DCR, PFS, and OS between groups. RESULTS Among the 14,902 initially identified papers, 98 studies regarding use of PD-1/PD-L1 inhibitors in advanced HCC were included. Based on different criteria of response in solid tumors, the pooled ORR, DCR, and median PFS was 16-36%, 54-74%, and 4.5-6.8 months, respectively. The pooled median OS was 11.9 months. Compared to multitarget tyrosine kinase inhibitors (TKIs), PD-1/PD-L1 inhibitors monotherapy significantly increased ORR (OR 2.73, P < 0.00001) and OS (HR 0.97, P = 0.05), and PD-1/PD-L1 inhibitors combined with TKIs significantly increased ORR (OR 3.17, P < 0.00001), DCR (OR 2.44, P < 0.00001), PFS (HR 0.58, P < 0.00001), and OS (HR 0.58, P < 0.00001). The pooled incidence of all-grade AEs, grade ≥ 3 AEs, and drug withdrawal was 71%, 25%, and 7%, respectively. CONCLUSION On the basis of the present systematic review and meta-analysis, PD-1/PD-L1 inhibitors should be the preferred treatment choice for advanced HCC owing to their higher antitumor effect and improved outcomes.
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Affiliation(s)
- Yuwei Liu
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, No. 83 Wenhua Road, Shenyang, 110840, Liaoning, People's Republic of China
- Postgraduate College, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China
| | - Jiahui Pan
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, No. 83 Wenhua Road, Shenyang, 110840, Liaoning, People's Republic of China
- Postgraduate College, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China
| | - Fangbo Gao
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, No. 83 Wenhua Road, Shenyang, 110840, Liaoning, People's Republic of China
- Postgraduate College, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China
| | - Wentao Xu
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, No. 83 Wenhua Road, Shenyang, 110840, Liaoning, People's Republic of China
- Postgraduate College, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China
| | - Hongyu Li
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, No. 83 Wenhua Road, Shenyang, 110840, Liaoning, People's Republic of China
| | - Xingshun Qi
- Liver Cirrhosis Study Group, Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, No. 83 Wenhua Road, Shenyang, 110840, Liaoning, People's Republic of China.
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Peng X, Gong C, Zhang W, Zhou A. Advanced development of biomarkers for immunotherapy in hepatocellular carcinoma. Front Oncol 2023; 12:1091088. [PMID: 36727075 PMCID: PMC9885011 DOI: 10.3389/fonc.2022.1091088] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 12/20/2022] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Mono-immunotherapy and combination therapy with immune checkpoint inhibitors (ICIs) and multitargeted tyrosine kinase inhibitors (TKIs) or anti-vascular endothelial growth factor (anti-VEGF) inhibitors have become new standard therapies in advanced HCC (aHCC). However, the clinical benefit of these treatments is still limited. Thus, proper biomarkers which can predict treatment response to immunotherapy to maximize clinical benefit while sparing unnecessary toxicity are urgently needed. Contrary to other malignancies, up until now, no acknowledged biomarkers are available to predict resistance or response to immunotherapy for HCC patients. Furthermore, biomarkers, which are established in other cancer types, such as programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB), have no stable predictive effect in HCC. Thus, plenty of research focusing on biomarkers for HCC is under exploration. In this review, we summarize the predictive and prognostic biomarkers as well as the potential predictive mechanism in order to guide future research direction for biomarker exploration and clinical treatment options in HCC.
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12
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Lei J, Chen B, Song M, Zhang L, Zhang X, Gao X, Li Y, Lu Y, Zuo S. TKI or TKI combined with PD-1 inhibitors as second-line treatment for HCC patients after sorafenib failure. Front Pharmacol 2022; 13:1026337. [PMID: 36569315 PMCID: PMC9782409 DOI: 10.3389/fphar.2022.1026337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
Background: Tyrosine kinase inhibitors (TKI) in combination with programmed cell death-1 (PD-1) inhibitors become the potential treatment modality for patients undergoing unresectable hepatocellular carcinoma (uHCC) in the first-line setting. However, the efficacy and safety of this combination regimen in patients after sorafenib failure remains unclear. Methods: Participants in this study included patients with uHCC after sorafenib failure who received TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors therapy (combination group) in our center from July 2018 to July 2021. The overall survival (OS) was used to be the primary efficacy endpoint, while progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were applied to be secondary endpoints. In addition, the adverse events are recorded and evaluated. Results: Among the 92 patients contained in this work, 50 patients were categorized into the TKI group, while 42 patients were in the combination group. There existed no evident differences between the two groups concerning the ORR (8.0% vs. 9.5%, p = 1.000). However, the DCR in the combined group was better in relative to that in the TKI group (71.4% vs. 50.0%, p = 0.037). In comparison with the TKI group, it was found that the combination group presented notably better median PFS (8.1 months vs. 4.7 months, p = 0.005) and median OS (21.9 months vs. 16.6 months, p = 0.042). According to multivariate analysis, PFS (HR 0.5, 95% CI: 0.3-0.8, p = 0.005) and OS (HR 0.5, 95% CI: 0.3-1.0, p = 0.051) were improved in the combination group in relative to the TKI group after the adjustment for some risk factors. Additionally, the incidence rates of grade ≥1 adverse event in the TKI group and the combination group were 96.0% and 97.6%, respectively. The most normal adverse event in the TKI group was neutropenia (n = 24,48.0%) and the combination group was hypoalbuminemia (n = 23,54.8%). All of these adverse events improved after symptomatic treatment, and no new toxic events were found to occur. Conclusion: TKI combined with PD-1 inhibitors showed better prognosis with manageable toxicity in uHCC patients after sorafenib failure compared with TKI monotherapy.
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Affiliation(s)
- Jin Lei
- Guizhou Medical University, Guiyang, China
| | - Bowen Chen
- Peking University 302 Clinical Medical School, Beijing, China
| | - Meiru Song
- The Fifth Medical Center of PLA General Hospital, The Fifth School of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Linzhi Zhang
- Comprehensive Liver Cancer Center, The Fifth Medical Center of the PLA General Hospita, Beijing, China
| | - Xinfeng Zhang
- The Fifth Medical Center of PLA General Hospital, The Fifth School of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Xiaoqiang Gao
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yinyin Li
- Comprehensive Liver Cancer Center, The Fifth Medical Center of the PLA General Hospita, Beijing, China
| | - Yinying Lu
- Guizhou Medical University, Guiyang, China
- Comprehensive Liver Cancer Center, The Fifth Medical Center of the PLA General Hospita, Beijing, China
- Guangdong Key Laboratory of Epigenetics, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China
| | - Shi Zuo
- Guizhou Medical University, Guiyang, China
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, China
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Huang JT, Zhang S, Yang YH, Zhang ZC, Jiang N, Li WC, Shen J, Zhong BY, Zhu XL. Recent Update on Immunotherapy and Its Combination With Interventional Therapies for Hepatocellular Carcinoma. Clin Med Insights Oncol 2022; 16:11795549221134832. [PMID: 36387611 PMCID: PMC9661563 DOI: 10.1177/11795549221134832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 10/10/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and deadly malignancies worldwide. Approximately, 80% of patients are initially diagnosed at intermediate or advanced stages, which means that curative therapies are unable to be performed. In most cases, systemic treatment is ineffective, especially when conventional cytotoxic agents are used. Sorafenib has been the only systemic agent proven to be effective in treating advanced HCC for over a decade. The rapid development of immunotherapy has remarkably revolutionized the management of advanced HCC. Besides, the combination of immunotherapy with molecular targeted agents or locoregional treatments is emerging as an effective tool for enhancing immunity. In the review, an overview of immunotherapy and its combination therapies for HCC is presented.
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Affiliation(s)
| | | | | | - Zi-Chen Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Nan Jiang
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Wan-Ci Li
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jian Shen
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | | | - Xiao-Li Zhu
- Xiao-Li Zhu, Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou 215006, Jiangsu, China.
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Li L, Liu HT, Teng YX, Deng ZJ, Zhang GL, Su JY, Ma L, Zhong JH. Second-line treatment options for hepatocellular carcinoma: current state and challenges for the future. Expert Opin Investig Drugs 2022; 31:1151-1167. [PMID: 36437752 DOI: 10.1080/13543784.2022.2151891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Since the approval of sorafenib for systemic treatment of advanced hepatocellular carcinoma (HCC), many tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have shown efficacy and tolerability as first-line treatments. On the other hand, these first-line therapies are associated with low objective response and drug resistance. Many drugs have been successfully tested for second-line treatment of advanced HCC. While the rapid proliferation of second-line treatments for advanced HCC brings hope to patients, it also complicates clinical decision-making. AREAS COVERED This review aims to facilitate decisions by summarizing the latest guidelines for second-line treatment of HCC in various countries or regions. We then review existing second-line treatment options and discuss challenges that should be addressed in the future. A literature search was conducted in April 2022 of PubMed/Medline, Cochrane library, and abstracts of international cancer meetings. EXPERT OPINION There is no standard second-line treatment, especially for the case of sequential treatment after atezolizumab plus bevacizumab (atezo+bev) and further studies focused on sequential treatment are warranted in this setting. The design of clinical trials, different etiologies, and complications or quality of life (QoL) are interesting issues in the second-line setting.
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Affiliation(s)
- Le Li
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Hao-Tian Liu
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yu-Xian Teng
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Zhu-Jian Deng
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Guan-Lan Zhang
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jia-Yong Su
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Liang Ma
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jian-Hong Zhong
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, Nanning, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education; Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Nanning, China
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15
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Zhu AX, Lin Y, Ferry D, Widau RC, Saha A. Surrogate end points for survival in patients with advanced hepatocellular carcinoma treated with immune checkpoint inhibitors. Immunotherapy 2022; 14:1341-1351. [PMID: 36285590 DOI: 10.2217/imt-2022-0089] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: The authors investigated surrogacy of radiology-based end points for clinical trials investigating immune checkpoint inhibitors in advanced hepatocellular carcinoma. Methods: Data were collected from electronic databases reporting median overall survival (OS), median progression-free survival (PFS) and objective response rate (ORR). Weighted Pearson correlation coefficients and 95% confidence intervals (CIs) were calculated. Results: 26 clinical trials (41 treatment arms, 5144 patients) were included. ORR (coefficient: 0.71; 95% CI: 0.52–0.84) and PFS (coefficient: 0.63; 95% CI: 0.21–0.92) were positively correlated with OS. Sensitivity analyses suggested liver function, line of therapy and study phase did not greatly impact results. The COSMIC-312 study negatively impacted the overall weighted correlation. Conclusion: ORR and PFS are positively correlated with OS in patients with advanced hepatocellular carcinoma.
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Affiliation(s)
- Andrew X Zhu
- Jiahui International Cancer Center, Jiahui Health, Shanghai, 200233, China
| | - Yong Lin
- Eli Lilly & Company, Indianapolis, IN 46225, USA
| | - David Ferry
- Eli Lilly & Company, Indianapolis, IN 46225, USA
| | - Ryan C Widau
- Eli Lilly & Company, Indianapolis, IN 46225, USA
| | - Abhijoy Saha
- Eli Lilly & Company, Indianapolis, IN 46225, USA
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Jin Z, Wu G, Xu B, Wang J, Zhu H, Guo Y, Peng M, Peng T, Wen Z. Case Report: Combining liver partition and portal vein ligation after thrombectomy for tumor isolation (CLAPT) to treat advanced hepatocellular carcinoma with portal vein tumor thrombosis. Front Surg 2022; 9:928452. [PMID: 36176342 PMCID: PMC9513360 DOI: 10.3389/fsurg.2022.928452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 08/25/2022] [Indexed: 01/27/2023] Open
Abstract
Background Primary liver cancer is the third leading cause of cancer-related deaths worldwide in 2020, and hepatocellular carcinoma (HCC) is the major pathological type. Patients with HCC complicated with portal vein tumor thrombosis (PVTT) have a poor prognosis, and controversies regarding treatment options exist among international scholars. Patients with VP4 or Cheng’s type III classification are generally considered ineligible for surgical treatment. Methods We retrospectively analyzed three cases of HCC with PVTT who underwent a novel modified surgical procedure. The procedure included portal vein thrombectomy and portal vein ligation with liver parenchymal separation for the resection of the tumor thrombus involving the main portal vein trunk and for the isolation of the giant tumor. The three cases were then treated with targeted drugs postoperatively. Results One case developed acute renal failure in the perioperative period, and the renal function gradually recovered after the treatment. The two remaining cases recovered uneventfully postoperatively. The prognosis of the three patients was encouraging. Only one patient died of lung metastasis after 13 months, and the remaining patients were still alive after 41 and 21 months, respectively. Conclusions We provide a new possible surgical option for patients with advanced HCC with PVTT. The surgical procedure was inspired by associating liver partition with portal vein ligation for staged hepatectomy and portal vein thrombectomy. The survival time was significantly prolonged after the patients underwent thrombectomy, tumor isolation, and postoperative nonsurgical treatment. Hence, the combination of liver partition and portal vein ligation after thrombectomy for tumor isolation has the potential for the treatment of advanced HCC with PVTT.
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Safety, efficacy, and tolerability of immune checkpoint inhibitors in the treatment of hepatocellular carcinoma. Surg Oncol 2022; 42:101748. [PMID: 35395582 DOI: 10.1016/j.suronc.2022.101748] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 02/20/2022] [Accepted: 03/22/2022] [Indexed: 12/29/2022]
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Abstract
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.
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Carloni R, Rizzo A, Ricci AD, Frega G, Federico AD, Palloni A, Marco MD, Gadaleta-Caldarola G, Brandi G. Dual immune checkpoint blockade in hepatocellular carcinoma: where do we stand? Future Oncol 2022; 18:1023-1034. [PMID: 35109664 DOI: 10.2217/fon-2021-0905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) represents the fourth most common cause of cancer-related death. Surgery, local ablative therapies and liver transplantation are the only potentially curative strategies, but the majority of patients present with advanced disease at diagnosis or develop recurrence after surgery. In recent years, immunotherapy for HCC has received growing interest, and one of the most promising strategies is the association of two immune checkpoint inhibitors (ICIs), which has already demonstrated its potential in other solid tumors such as melanoma and renal cell carcinoma. Herein, we discuss the role and the biologic rationale of dual immune checkpoint blockade in HCC patients, focusing on the two ICI combinations: nivolumab plus ipilimumab and durvalumab plus tremelimumab.
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Affiliation(s)
- Riccardo Carloni
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
| | - Alessandro Rizzo
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy.,Medical Oncology Unit, 'Mons. R. Dimiccoli' Hospital, Barletta (BT), Azienda Sanitaria Locale Barletta, 76121, Italy
| | - Angela Dalia Ricci
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy.,Medical Oncology Unit, 'Mons. R. Dimiccoli' Hospital, Barletta (BT), Azienda Sanitaria Locale Barletta, 76121, Italy
| | - Giorgio Frega
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
| | - Alessandro Di Federico
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
| | - Andrea Palloni
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
| | - Mariacristina Di Marco
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
| | - Gennaro Gadaleta-Caldarola
- Medical Oncology Unit, 'Mons. R. Dimiccoli' Hospital, Barletta (BT), Azienda Sanitaria Locale Barletta, 76121, Italy
| | - Giovanni Brandi
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni 15, Bologna, Italy
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20
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Zhang L, Geng Z, Hao B, Geng Q. Tislelizumab: A Modified Anti-tumor Programmed Death Receptor 1 Antibody. Cancer Control 2022; 29:10732748221111296. [PMID: 35926155 PMCID: PMC9358212 DOI: 10.1177/10732748221111296] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Tislelizumab is an anti-programmed death receptor 1 (PD-1) monoclonal immunoglobulin G 4 antibody developed by BeiGene. The structure of tislelizumab has been modified to maximally inhibit the binding of PD-1 to programmed death ligand 1 (PD-L1) and minimize the binding of tislelizumab to Fcγ receptors. In clinical studies, tislelizumab has shown preliminary anti-tumor effects in various solid tumors, such as Hodgkin's lymphoma, urothelial carcinoma, lung cancer, gastric and esophageal cancer, liver cancer, nasopharyngeal carcinoma, colorectal cancer, and microsatellite instability-high/mismatch repair-deficient tumors. In addition, it also showed new promise in solid tumor treatment in combination with ociperlimab. Due to its satisfactory anti-tumor effects, tislelizumab has received approvals in China for the treatment of classical Hodgkin's lymphoma, urothelial carcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and hepatocellular carcinoma, and it is now under investigation for a new indication in microsatellite instability-high/mismatch repair-deficient tumors. Moreover, it has been granted orphan designations in hepatocellular carcinoma, esophageal cancer, and gastric cancer, including cancer of the gastroesophageal junction, by the US Food and Drug Administration. Tislelizumab has an acceptable safety profile; the most common adverse effects include fatigue, anemia, and decreased neutrophil count, while the most fatal events have been related to respiratory infection or failure, and hepatic injury. Tislelizumab has an economic advantage compared with other well-studied PD-1/PD-L1 inhibitors; thus, the introduction of it could provide clinical oncologists with an effective weapon against tumors and may alleviate the burden of cancer patients.
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Affiliation(s)
- Lin Zhang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhihua Geng
- Department of Orthopedic Surgery, Wuhan Fourth Hospital, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bo Hao
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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21
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Sun HC, Zhu XD. Downstaging Conversion Therapy in Patients With Initially Unresectable Advanced Hepatocellular Carcinoma: An Overview. Front Oncol 2021; 11:772195. [PMID: 34869008 PMCID: PMC8636437 DOI: 10.3389/fonc.2021.772195] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 10/28/2021] [Indexed: 12/12/2022] Open
Abstract
The high mortality rate associated with hepatocellular carcinoma (HCC) is partly due to the high proportion of patients who present with advanced stage disease at diagnosis, for whom there are limited treatment options. For selected patients with initially unresectable HCC, locoregional and/or systemic treatments can result in tumor downstaging and consequently provide opportunities for surgical intervention and the potential for long-term survival. Therefore, the key aim of 'conversion therapy' is to reduce tumor burden so that patients become amenable to surgical resection. Various therapies have been investigated as candidates for downstaging patients with potentially resectable HCC including transarterial chemoembolization, transarterial radioembolization with yttrium-90 microspheres, radiotherapy, systemic therapies and combination or multimodality treatment approaches. However, downstaging conversion therapy remains controversial and there are several challenges such as defining the criteria used to identify the population of patients who are 'potentially resectable', the criteria used to define successful downstaging, and the optimum treatment approach to maximize the success of downstaging therapy. In this review article, we summarize clinical experience and evidence of downstaging conversion treatment in patients identified as having 'potentially resectable' HCC.
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Affiliation(s)
- Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, China
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22
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Liu Z, Liu X, Liang J, Liu Y, Hou X, Zhang M, Li Y, Jiang X. Immunotherapy for Hepatocellular Carcinoma: Current Status and Future Prospects. Front Immunol 2021; 12:765101. [PMID: 34675942 PMCID: PMC8524467 DOI: 10.3389/fimmu.2021.765101] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with poor prognosis. Surgery, chemotherapy, and radiofrequency ablation are three conventional therapeutic options that will help only a limited percentage of HCC patients. Cancer immunotherapy has achieved dramatic advances in recent years and provides new opportunities to treat HCC. However, HCC has various etiologies and can evade the immune system through multiple mechanisms. With the rapid development of genetic engineering and synthetic biology, a variety of novel immunotherapies have been employed to treat advanced HCC, including immune checkpoint inhibitors, adoptive cell therapy, engineered cytokines, and therapeutic cancer vaccines. In this review, we summarize the current landscape and research progress of different immunotherapy strategies in the treatment of HCC. The challenges and opportunities of this research field are also discussed.
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Affiliation(s)
- Zhuoyan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xuan Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaxin Liang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yixin Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xiaorui Hou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Meichuan Zhang
- R&D Department, Caleb BioMedical Technology Co. Ltd, Guangzhou, China
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaotao Jiang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.,Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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