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Wan Q, Zhao C, Zhao R. Progress of Pyruvate Kinase M2 in Hepatocellular Carcinoma-Associated Signaling Pathway. Tissue Eng Part C Methods 2025; 31:101-107. [PMID: 40105913 DOI: 10.1089/ten.tec.2024.0368] [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] [Indexed: 03/21/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive liver tumor with a unique metabolic profile and a shift to glycolytic metabolism. This review discusses the contribution of pyruvate kinase M2 (PKM2) to HCC development and its potential as a target for therapy. We carried out a broad literature review on PKM2, focusing on its role in the glycolytic pathway and special interactions with key signaling pathways like Phosphoinositide 3-kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) and Mitogen-activated protein kinase (MAPK). PKM2 also performs a dual role in energy metabolism and signal transduction in HCC. PKM2 is paramount in the induction of HCC by regulating cellular metabolism and oncogenic signaling pathways. It promotes tumor growth, survival, and metastasis through interaction with the PI3K/AKT/mTOR and MAPK pathways. PKM2 is a key factor in HCC pathogenesis, with a dual impact on metabolism and signaling. Its properties may open the way for developing novel therapeutic interventions against HCC. Thus, PKM2 inhibition may offer further opportunities for tumor growth blockade, which could meaningfully improve patients' clinical outcomes.
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Affiliation(s)
- Qi Wan
- Second Hospital of Lanzhou University, Lanzhou, China
| | - Chunlian Zhao
- Second Hospital of Lanzhou University, Lanzhou, China
| | - Rui Zhao
- Second Hospital of Lanzhou University, Lanzhou, China
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Kobayashi K, Ogasawara S, Itobayashi E, Okubo T, Itokawa N, Nakamura K, Moriguchi M, Watanabe S, Ikeda M, Kuroda H, Kawaoka T, Hiraoka A, Yasui Y, Kuzuya T, Sato R, Kanzaki H, Koroki K, Inoue M, Nakamura M, Kiyono S, Kanogawa N, Kondo T, Nakamoto S, Ozawa Y, Tsuchiya K, Atsukawa M, Aikata H, Aramaki T, Oka S, Morimoto N, Kurosaki M, Itoh Y, Izumi N, Kato N. Ramucirumab for advanced hepatocellular carcinoma in the current real world: a Japanese single-arm study post-REACH-2 (The R-evolution study). Invest New Drugs 2024; 42:394-404. [PMID: 38842657 PMCID: PMC11327193 DOI: 10.1007/s10637-024-01441-3] [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: 03/12/2024] [Accepted: 04/26/2024] [Indexed: 06/07/2024]
Abstract
This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.
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Affiliation(s)
- Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Norio Itokawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | | | - Michihisa Moriguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shunji Watanabe
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hidekatsu Kuroda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Teiji Kuzuya
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Rui Sato
- Division of Interventional Radiology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masanori Inoue
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshihito Ozawa
- Biostatistics Section, Clinical Research Center, Chiba University, Chiba, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
- Department of Gastroenterology, Hiroshima Prefectural Hospital, Hiroshima, Japan
| | - Takeshi Aramaki
- Division of Interventional Radiology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Shiro Oka
- Department of Gastroenterology and Metabolism, Hiroshima University Hospital, Hiroshima, Japan
| | - Naoki Morimoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Yoshito Itoh
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
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Majeed A, Alaparthi S, Halegoua-DeMarzio D, Eberle-Singh J, Jiang W, Anne PR, Shah AP, Bowne WB, Lin D. Complete Pathologic Response to Gemcitabine and Oxaliplatin Chemotherapy After Prior Therapies in a Patient With Hepatocellular Carcinoma and Peritoneal Metastases Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. World J Oncol 2024; 15:511-520. [PMID: 38751709 PMCID: PMC11092419 DOI: 10.14740/wjon1840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 05/01/2024] [Indexed: 05/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is often diagnosed at a late stage and frequently recurs despite curative intervention, leading to poor survival outcomes. Frontline systemic therapies include combination immunotherapy regimens and tyrosine kinase inhibitors. We report a case of a 38-year-old woman with chronic hepatitis B and C coinfection-associated non-cirrhotic HCC, which recurred in the peritoneum after initial resection of her primary tumor. Disease progression occurred on both atezolizumab/bevacizumab and lenvatinib, and she was subsequently treated with gemcitabine and oxaliplatin (GEMOX) chemotherapy and exhibited a profound clinical response on imaging with normalization of alpha fetoprotein (AFP) after several months. Following extensive multidisciplinary discussion, she underwent cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) that removed all visible macroscopic tumor. Her pathology demonstrated a complete pathologic response. She received two additional months of postoperative chemotherapy, and then proceeded with close monitoring off therapy. To our knowledge, this is the first reported case of a complete pathologic response to GEMOX chemotherapy in the context of CRS/HIPEC for peritoneal metastases in HCC, after progression on standard immunotherapy and tyrosine kinase inhibitor treatments. In this report, we review the current systemic treatment landscape in HCC. We highlight potential consideration of cytotoxic chemotherapy, which is less frequently utilized in current practice, in selected patients with HCC, and discuss the role of CRS/HIPEC in the management of peritoneal metastases. Further investigation regarding predictors of response to systemic treatments is strongly needed. Multidisciplinary management may ultimately prolong survival in patients with advanced HCC.
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Affiliation(s)
- Amry Majeed
- Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Sneha Alaparthi
- Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Dina Halegoua-DeMarzio
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Jaime Eberle-Singh
- Department of Pathology and Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Wei Jiang
- Department of Pathology and Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Pramila Rani Anne
- Department of Radiation Oncology, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Ashesh P. Shah
- Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Wilbur B. Bowne
- Department of General Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, USA
| | - Daniel Lin
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA, USA
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Galasso L, Cerrito L, Maccauro V, Termite F, Ainora ME, Gasbarrini A, Zocco MA. Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress. Cancers (Basel) 2024; 16:1837. [PMID: 38791916 PMCID: PMC11119751 DOI: 10.3390/cancers16101837] [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: 04/16/2024] [Revised: 04/30/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Hepatocellular carcinoma is a malignant tumor that originates from hepatocytes in an inflammatory substrate due to different degrees of liver fibrosis up to cirrhosis. In recent years, there has been growing interest in the role played by the complex interrelationship between hepatocellular carcinoma and its microenvironment, capable of influencing tumourigenesis, neoplastic growth, and its progression or even inhibition. The microenvironment is made up of an intricate network of mesenchymal cells, immune system cells, extracellular matrix, and growth factors, as well as proinflammatory cytokines and translocated bacterial products coming from the intestinal microenvironment via the enterohepatic circulation. The aim of this paper is to review the role of the HCC microenvironment and describe the possible implications in the choice of the most appropriate therapeutic scheme in the prediction of tumor response or resistance to currently applied treatments and in the possible development of future therapeutic perspectives, in order to circumvent resistance and break down the tumor's defensive fort.
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Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Valeria Maccauro
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy (L.C.); (V.M.); (A.G.)
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
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Wu TKH, Hui RWH, Mak LY, Fung J, Seto WK, Yuen MF. Hepatocellular carcinoma: Advances in systemic therapies. F1000Res 2024; 13:104. [PMID: 38766497 PMCID: PMC11099512 DOI: 10.12688/f1000research.145493.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/23/2024] [Indexed: 05/22/2024] Open
Abstract
Advanced hepatocellular carcinoma (HCC) is traditionally associated with limited treatment options and a poor prognosis. Sorafenib, a multiple tyrosine kinase inhibitor, was introduced in 2007 as a first-in-class systemic agent for advanced HCC. After sorafenib, a range of targeted therapies and immunotherapies have demonstrated survival benefits in the past 5 years, revolutionizing the treatment landscape of advanced HCC. More recently, evidence of novel combinations of systemic agents with distinct mechanisms has emerged. In particular, combination trials on atezolizumab plus bevacizumab and durvalumab plus tremelimumab have shown encouraging efficacy. Hence, international societies have revamped their guidelines to incorporate new recommendations for these novel systemic agents. Aside from treatment in advanced HCC, the indications for systemic therapy are expanding. For example, the combination of systemic therapeutics with locoregional therapy (trans-arterial chemoembolization or stereotactic body radiation therapy) has demonstrated promising early results in downstaging HCC. Recent trials have also explored the role of systemic therapy as neoadjuvant treatment for borderline-resectable HCC or as adjuvant treatment to reduce recurrence risk after curative resection. Despite encouraging results from clinical trials, the real-world efficacy of systemic agents in specific patient subgroups (such as patients with advanced cirrhosis, high bleeding risk, renal impairment, or cardiometabolic diseases) remains uncertain. The effect of liver disease etiology on systemic treatment efficacy warrants further research. With an increased understanding of the pathophysiological pathways and accumulation of clinical data, personalized treatment decisions will be possible, and the field of systemic treatment for HCC will continue to evolve.
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Affiliation(s)
- Trevor Kwan-Hung Wu
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Rex Wan-Hin Hui
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong
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Vogel A, Kelley RK, Johnson P, Merle P, Yau T, Kudo M, Meyer T, Rimassa L. Predictive and Prognostic Potential of Liver Function Assessment in Patients with Advanced Hepatocellular Carcinoma: A Systematic Literature Review. Liver Cancer 2023; 12:372-391. [PMID: 37817754 PMCID: PMC10561324 DOI: 10.1159/000529173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 12/15/2022] [Indexed: 10/12/2023] Open
Abstract
Introduction We conducted a systematic literature review to assess the utility of liver function assessments for predicting disease prognosis and response to systemic anticancer therapy in patients with advanced hepatocellular carcinoma (aHCC). Methods This was a PRISMA-standard review and was registered with PROSPERO (CRD42021244588). MEDLINE and Embase were systematically searched (March 24, 2021) to identify publications reporting the efficacy and/or safety of systemic anticancer therapy (vs. any/no comparator) in liver-function-defined subgroups in phase 2 or 3 aHCC trials. Screening was completed by a single reviewer, with uncertainties resolved by a second reviewer and/or the authors. English-language full-text articles and congress abstracts were eligible for inclusion. Included publications were described and assessed for risk of bias using the GRADE methodology. Results Twenty (of 2,579) screened publications were eligible; seven categorized liver function using the albumin-bilirubin system, nine using the Child-Pugh system, four using both. GRADE assessment classified ten, nine, and one publication(s) as reporting moderate-quality, low-quality, and very-low-quality evidence, respectively. Analyses of cross-trial trends of within-exposure arm analyses (active and control) reported a positive relationship between baseline liver function and overall survival and progression-free survival, supporting liver function as a prognostic marker in aHCC. There were also signals for a modest relationship between more preserved baseline liver function and extent of systemic treatment benefit, and with more preserved liver function and lower incidence of safety events. Conclusion This review supports liver function as a prognostic variable in aHCC and highlights the value of a priori stratification of patients by baseline liver function in aHCC trials. The predictive value of liver function warrants further study. Findings were limited by the quality of available data.
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Affiliation(s)
- Arndt Vogel
- Department of Klinik für Gastroenterology, Hannover Medical School, Hannover, Germany
| | - Robin K. Kelley
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, California, USA
| | - Philip Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Philippe Merle
- Hepatology and Gastroenterology Unit, Hôpital de la Croix Rousse, Lyon, France
| | | | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University, Osaka-Sayama, Japan
| | - Tim Meyer
- Research Department of Oncology, UCL Cancer Institute, University College London, London, UK
- Royal Free Hospital, London, UK
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele (Milan), Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano (Milan), Italy
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Motomura K, Kuwano A, Tanaka K, Koga Y, Masumoto A, Yada M. Potential Predictive Biomarkers of Systemic Drug Therapy for Hepatocellular Carcinoma: Anticipated Usefulness in Clinical Practice. Cancers (Basel) 2023; 15:4345. [PMID: 37686621 PMCID: PMC10486942 DOI: 10.3390/cancers15174345] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
In the systemic drug treatment of hepatocellular carcinoma, only the tyrosine kinase inhibitor (TKI) sorafenib was available for a period. This was followed by the development of regorafenib as a second-line treatment after sorafenib, and then lenvatinib, a new TKI, proved non-inferiority to sorafenib and became available as a first-line treatment. Subsequently, cabozantinib, another TKI, was introduced as a second-line treatment, along with ramucirumab, the only drug proven to be predictive of therapeutic efficacy when AFP levels are >400 ng/mL. It is an anti-VEGF receptor antibody. More recently, immune checkpoint inhibitors have become the mainstay of systemic therapy and can now be used as a first-line standard treatment for HCC. However, the objective response rate for these drugs is currently only 30% to 40%, and there is a high incidence of side effects. Additionally, there are no practical biomarkers to predict their therapeutic effects. Therefore, this review provides an overview of extensive research conducted on potential HCC biomarkers from blood, tissue, or imaging information that can be used in practice to predict the therapeutic efficacy of systemic therapy before its initiation.
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Affiliation(s)
- Kenta Motomura
- Department of Hepatology, Iizuka Hospital, 3-83 Yoshio-machi, Iizuka, Fukuoka 820-8505, Japan; (A.K.); (K.T.); (Y.K.); (A.M.); (M.Y.)
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8
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Zheng Y, Zhong H, Zhao F, Zhou H, Mao C, Lv W, Yuan M, Qian J, Jiang H, Wang Z, Xiao C, Guo J, Liu T, Liu W, Wang ZM, Li B, Xia M, Xu N. First-in-human, phase I study of AK109, an anti-VEGFR2 antibody in patients with advanced or metastatic solid tumors. ESMO Open 2023; 8:101156. [PMID: 36989884 PMCID: PMC10163150 DOI: 10.1016/j.esmoop.2023.101156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 03/29/2023] Open
Abstract
BACKGROUND Vascular endothelial growth factor receptor 2 (VEGFR2) plays a key role in antiangiogenesis which has been an essential strategy for cancer treatment. We report the first-in-human study of AK109, a novel anti-VEGFR2 monoclonal antibody, to characterize the safety profile and pharmacokinetics/pharmacodynamics (PK/PD) properties, and explore the preliminary antitumor efficacy in patients with solid tumors. PATIENTS AND METHODS This was a multicenter, open-label, phase I study, including dose escalation and dose expansion (NCT04547205). Patients with advanced cancers were treated 2 and 3 weekly with escalating doses of AK109. A 3 + 3 design was used to determine the maximum tolerated dose. Blood was sampled for PK/PD analysis. The primary endpoint was safety and recommended phase II dose (RP2D). RESULTS A total of 40 patients were enrolled. No dose-limiting toxicity was observed. However, 38 patients reported treatment-related adverse events (TRAEs); grade ≥3 TRAEs occurred in 10 patients. The most common TRAEs were proteinuria (n = 24, 60%), hypertension (n = 13, 32.5%), increased aspartate transaminase (n = 11, 27.5%), thrombopenia (n = 10, 25%), and anemia (n = 10, 25%). A total of 28 patients (70%) reported adverse events of special interest (AESIs). The most common AESIs were proteinuria (60%), hypertension (32.5%), and hemorrhage (32.5%), mainly including gum bleeding and urethrorrhagia. AK109 exhibited an approximately linear PK exposure with dose escalation at 2-12 mg/kg. PD analyses showed rapid target engagement. Among the 40 patients, 4 achieved partial response and 21 achieved stable disease with an objective response rate of 10% and a disease control rate of 62.5%. Based on the safety profile, the PK/PD profile, and preliminary antitumor activities, 12 mg/kg Q2W and 15 mg/kg Q3W were selected as RP2D. CONCLUSIONS AK109 showed manageable safety profile and promising antitumor activity, supporting further clinical development in a large population.
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Affiliation(s)
- Y Zheng
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - H Zhong
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou
| | - F Zhao
- The First Affiliated Hospital, Bengbu Medical College, Bengbu
| | - H Zhou
- The First Affiliated Hospital, Bengbu Medical College, Bengbu
| | - C Mao
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - W Lv
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou
| | - M Yuan
- The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou
| | - J Qian
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - H Jiang
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Z Wang
- The First Affiliated Hospital, Bengbu Medical College, Bengbu
| | - C Xiao
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - J Guo
- Akeso Biopharma, Inc., Zhongshan, China
| | - T Liu
- Akeso Biopharma, Inc., Zhongshan, China
| | - W Liu
- Akeso Biopharma, Inc., Zhongshan, China
| | - Z M Wang
- Akeso Biopharma, Inc., Zhongshan, China
| | - B Li
- Akeso Biopharma, Inc., Zhongshan, China
| | - M Xia
- Akeso Biopharma, Inc., Zhongshan, China
| | - N Xu
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou.
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Leowattana W, Leowattana T, Leowattana P. Systemic treatment for unresectable hepatocellular carcinoma. World J Gastroenterol 2023; 29:1407-1424. [DOI: 10.3748/wjg.v29.i10.1407] [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] [Indexed: 03/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease. Advanced HCC has a poor prognosis. For many years, the only proven therapy for unresectable HCC (uHCC) was sorafenib, a tyrosine kinase inhibitor. Recently, the synergistic effect of an immune checkpoint inhibitor, atezolizumab, and bevacizumab outperformed sorafenib alone in terms of survival, making it the recommended first-line therapy. Other multikinase inhibitors, lenvatinib and regorafenib, were also recommended as first and second-line drugs, respectively. Intermediate-stage HCC patients with retained liver function, particularly uHCC without extrahepatic metastasis, may benefit from trans-arterial chemoembolization. The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function. Indeed, all study patients had a Child-Pugh class A, and the best therapy for other individuals is unknown. Additionally, in the absence of a medical contraindication, atezolizumab could be combined with bevacizumab for uHCC systemic therapy. Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs, and the first findings are encouraging. The paradigm of uHCC therapy is changing dramatically, and many obstacles remain for optimum patient management in the near future. The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - PathompThep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
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10
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Leowattana W, Leowattana T, Leowattana P. Systemic treatment for unresectable hepatocellular carcinoma. World J Gastroenterol 2023; 29:1551-1568. [PMID: 36970588 PMCID: PMC10037251 DOI: 10.3748/wjg.v29.i10.1551] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 01/08/2023] [Accepted: 02/22/2023] [Indexed: 03/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease. Advanced HCC has a poor prognosis. For many years, the only proven therapy for unresectable HCC (uHCC) was sorafenib, a tyrosine kinase inhibitor. Recently, the synergistic effect of an immune checkpoint inhibitor, atezolizumab, and bevacizumab outperformed sorafenib alone in terms of survival, making it the recommended first-line therapy. Other multikinase inhibitors, lenvatinib and regorafenib, were also recommended as first and second-line drugs, respectively. Intermediate-stage HCC patients with retained liver function, particularly uHCC without extrahepatic metastasis, may benefit from trans-arterial chemoembolization. The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function. Indeed, all study patients had a Child-Pugh class A, and the best therapy for other individuals is unknown. Additionally, in the absence of a medical contraindication, atezolizumab could be combined with bevacizumab for uHCC systemic therapy. Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs, and the first findings are encouraging. The paradigm of uHCC therapy is changing dramatically, and many obstacles remain for optimum patient management in the near future. The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - PathompThep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
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11
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Farasati Far B, Rabie D, Hemati P, Fooladpanjeh P, Faal Hamedanchi N, Broomand Lomer N, Karimi Rouzbahani A, Naimi-Jamal MR. Unresectable Hepatocellular Carcinoma: A Review of New Advances with Focus on Targeted Therapy and Immunotherapy. LIVERS 2023; 3:121-160. [DOI: 10.3390/livers3010011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
With an expected incidence of more than 1 million cases by 2025, liver cancer remains a problem for world health. With over 90% of cases, hepatocellular carcinoma (HCC) is the most prevalent kind of liver cancer. In this review, we presented the range of experimental therapeutics for patients with advanced HCC, the successes and failures of new treatments, areas for future development, the evaluation of dose-limiting toxicity in different drugs, and the safety profile in patients with liver dysfunction related to the underlying chronic liver disease. In addition to the unmet demand for biomarkers to guide treatment decisions and the burgeoning fields of immunotherapy and systemic therapy in hepatocellular carcinoma, the development of old and new drugs, including their failures and current advancements, has been reviewed. This review aims to evaluate the updated optimal clinical treatment of unresectable hepatocellular carcinomas in clinical practice, mainly through targeted therapy. Although surgical treatment can significantly enhance the survival probability of early and intermediate-stage patients, it is unsuitable for most HCC patients due to a lack of donors. Due to their severe toxicity, the few first-line anti-HCC drugs, such as sorafenib, are often reserved for advanced HCC patients for whom other therapies have failed. The second-line drugs are usually alternatives for patients with intolerance or resistance. Consequently, the ongoing growth of possible preclinical drugs and studies on miRNAs, lncRNAs, and numerous other signaling pathway targets for developing novel drugs may introduce additional treatment prospects for HCC.
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Affiliation(s)
- Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran 1684613114, Iran
| | - Dorsa Rabie
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Parisa Hemati
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Parastoo Fooladpanjeh
- Faculty of Pharmaceutical Chemistry, Tehran Medical Sciences, Islamic Azad University, Tehran 193951495, Iran
| | - Neda Faal Hamedanchi
- Faculty of Medicine, Islamic Azad University, Tehran Medical Sciences Branch, Tehran 193951495, Iran
| | - Nima Broomand Lomer
- Faculty of Medicine, Guilan University of Medical Sciences, Rasht 4314637758, Iran
| | - Arian Karimi Rouzbahani
- Student Research Committee, Lorestan University of Medical Sciences, Khorramabad 6718773654, Iran
- USERN Office, Lorestan University of Medical Sciences, Khorramabad 6718773654, Iran
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12
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Kanogawa N, Ogasawara S, Maruta S, Iino Y, Obu M, Ishino T, Ogawa K, Yumita S, Iwanaga T, Unozawa H, Nakagawa M, Fujiwara K, Sakuma T, Fujita N, Kojima R, Kanzaki H, Koroki K, Kobayashi K, Inoue M, Kiyono S, Nakamura M, Kondo T, Saito T, Nakagawa R, Nakamoto S, Muroyama R, Chiba T, Itobayashi E, Koma Y, Azemoto R, Kato J, Kato N. Use of ramucirumab for various treatment lines in real-world practice of patients with advanced hepatocellular carcinoma. BMC Gastroenterol 2023; 23:70. [PMID: 36906542 PMCID: PMC10007811 DOI: 10.1186/s12876-023-02674-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 02/13/2023] [Indexed: 03/13/2023] Open
Abstract
PURPOSE Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. METHODS Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. RESULTS A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3). CONCLUSION Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.
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Affiliation(s)
- Naoya Kanogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Sadahisa Ogasawara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan.
| | - Susumu Maruta
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Yotaro Iino
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Japan
| | - Masamichi Obu
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Japan
| | - Takamasa Ishino
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Keita Ogawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Sae Yumita
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Terunao Iwanaga
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hidemi Unozawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Miyuki Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Kisako Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Takafumi Sakuma
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Naoto Fujita
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Ryuta Kojima
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hiroaki Kanzaki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Keisuke Koroki
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Kazufumi Kobayashi
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Masanori Inoue
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Soichiro Kiyono
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Masato Nakamura
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Takayuki Kondo
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Tomoko Saito
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Ryo Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Ryosuke Muroyama
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Yoshihiro Koma
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Japan
| | - Ryosaku Azemoto
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
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13
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Finn RS, Yau T, Hsu CH, De Toni EN, Goyal L, Galle PR, Qin S, Rao S, Sun F, Wang C, Widau RC, Zhu AX. Ramucirumab for Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha Fetoprotein Following Non-Sorafenib Systemic Therapy: An Expansion Cohort of REACH-2. Oncologist 2022; 27:e938-e948. [PMID: 36190331 DOI: 10.1093/oncolo/oyac183] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/05/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ramucirumab is indicated for patients with advanced hepatocellular carcinoma (HCC) and α-fetoprotein (AFP) ≥400 ng/mL following sorafenib. Here, we prospectively studied ramucirumab following non-sorafenib systemic therapies. MATERIALS AND METHODS This open-label, non-comparative cohort of REACH-2 enrolled patients with advanced HCC, Child-Pugh class-A liver disease, and AFP ≥400 ng/mL who had received 1-2 lines of therapy, excluding sorafenib or chemotherapy. Ramucirumab was administered 8 mg/kg intravenously Q2W. The primary endpoint was safety. Secondary endpoints were overall survival, progression-free survival, objective response rate (RECIST v1.1), time to progression, pharmacokinetics, and patient-reported outcomes. Final analysis occurred after all enrolled patients completed ≥3 treatment cycles or discontinued treatment. RESULTS Between April 27, 2018, and March 29, 2021, 47 patients were treated at 21 investigative sites in Asia, Europe, and USA. The most frequently reported grade ≥3 adverse events, regardless of causality, were hypertension (11%), proteinuria (6%), hyponatremia (6%), and AST increased (6%). Two patients died from adverse events (myocardial infarction and upper gastrointestinal hemorrhage), deemed related to treatment. Median progression-free survival, time to progression, and overall survival were 1.7 months, 2.8 months, and 8.7 months, respectively. The objective response rate was 10.6% with a median duration response of 8.3 months. Median time to deterioration in FHSI-8 total score was 4.4 months. CONCLUSION Ramucirumab demonstrated consistent and meaningful clinical activity with no new safety signals following non-sorafenib therapies in patients with advanced HCC and AFP ≥400 ng/mL. This represents one of the first sequencing studies for patients with advanced HCC not treated with sorafenib.
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Affiliation(s)
| | - Thomas Yau
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Chih-Hung Hsu
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Enrico N De Toni
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Lipika Goyal
- Department of Medicine, Mass General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Peter R Galle
- Department of Internal Medicine, University Medical Center Mainz, Mainz, Germany
| | - ShuKui Qin
- Department of Medical Oncology, People's Liberation Army Cancer Center, Nanjing Bayi Hospital, Nanjing, People's Republic of China
| | - Sujata Rao
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | | | | | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.,Jiahui International Cancer Center, Jiahui Health, Shanghai, People's Republic of China
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14
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Shannon AH, Ruff SM, Pawlik TM. Expert Insights on Current Treatments for Hepatocellular Carcinoma: Clinical and Molecular Approaches and Bottlenecks to Progress. J Hepatocell Carcinoma 2022; 9:1247-1261. [PMID: 36514693 PMCID: PMC9741819 DOI: 10.2147/jhc.s383922] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/18/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver tumor that typically occurs in the setting of chronic liver disease/cirrhosis. Treatment modalities for HCC have evolved and given the variety of treatment options, a multi-disciplinary approach requiring input from surgical, medical, and radiation oncology, hepatology, and interventional radiology is necessary. Multiple advances have been made over the last decade regarding treatment of HCC, especially advanced disease. Resection and transplantation remain as cornerstone curative-intent treatment options. For patients who are not candidates for curative-intent therapy, exciting progress has been made in molecular and cellular approaches to systemic therapy for HCC including immunotherapies and tyrosine kinase inhibitors. Although the prognosis for advanced HCC remains poor, the armamentarium of therapies has increased, and valuable years of life can be gained with these therapies. While the main therapeutic modality for early-stage disease remains resection, multimodal immunotherapy has emerged as first-line treatment for advanced disease. We herein review different clinical and molecular treatment modalities related to the treatment of HCC, as well as provide insights into future directions for HCC treatment. We highlight how research and progress are needed to move into a new era of molecular and cellular treatments.
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Affiliation(s)
- Alexander H Shannon
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Samantha M Ruff
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA,Correspondence: Timothy M Pawlik, Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Professor of Surgery, Oncology, Health Services Management and Policy, The Ohio State University, Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH, USA, Tel +1 614 293 8701, Fax +1 614 293 4063, Email
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15
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Damaskos C, Garmpis N, Dimitroulis D, Garmpi A, Psilopatis I, Sarantis P, Koustas E, Kanavidis P, Prevezanos D, Kouraklis G, Karamouzis MV, Marinos G, Kontzoglou K, Antoniou EA. Targeted Therapies for Hepatocellular Carcinoma Treatment: A New Era Ahead-A Systematic Review. Int J Mol Sci 2022; 23:14117. [PMID: 36430594 PMCID: PMC9698799 DOI: 10.3390/ijms232214117] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains one of the most common malignancies and the third cause of cancer-related death worldwide, with surgery being the best prognostic tool. Among the well-known causative factors of HCC are chronic liver virus infections, chronic virus hepatitis B (HBV) and chronic hepatitis virus C (HCV), aflatoxins, tobacco consumption, and non-alcoholic liver disease (NAFLD). There is a need for the development of efficient molecular markers and alternative therapeutic targets of great significance. In this review, we describe the general characteristics of HCC and present a variety of targeted therapies that resulted in progress in HCC therapy.
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Affiliation(s)
- Christos Damaskos
- Renal Transplantation Unit, Laiko General Hospital, 11527 Athens, Greece
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Nikolaos Garmpis
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Dimitrios Dimitroulis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Anna Garmpi
- First Department of Propedeutic Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Iason Psilopatis
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt—Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Prodromos Kanavidis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | | | - Gregory Kouraklis
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Michail V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Marinos
- Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Konstantinos Kontzoglou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Efstathios A. Antoniou
- Nikolaos Christeas Laboratory of Experimental Surgery and Surgical Research, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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16
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O'Melia MJ, Rohner NA, Thomas SN. Tumor Vascular Remodeling Affects Molecular Dissemination to Lymph Node and Systemic Leukocytes. Tissue Eng Part A 2022; 28:781-794. [PMID: 35442085 PMCID: PMC9508451 DOI: 10.1089/ten.tea.2022.0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 04/13/2022] [Indexed: 11/13/2022] Open
Abstract
Angiogenic and lymphangiogenic remodeling has long been accepted as a hallmark of cancer development and progression; however, the impacts of this remodeling on immunological responses, which are paramount to the responses to immunotherapeutic treatments, are underexplored. As immunotherapies represent one of the most promising new classes of cancer therapy, in this study, we explore the effects of angiogenic and lymphangiogenic normalization on dissemination of molecules injected into the tumor microenvironment to immune cells in lymph nodes draining the tumor as well as in systemically distributed tissues. A system of fluorescent tracers, size-matched to biomolecules of interest, was implemented to track different mechanisms of tumor transport and access to immune cells. This revealed that the presence of a tumor, and either angiogenic or lymphangiogenic remodeling, altered local retention of model biomolecules, trended toward normalizing dissemination to systemic organs, and modified access to lymph node-resident immune cells in manners dependent on mechanism of transport. More specifically, active cell migration by skin-derived antigen presenting cells was enhanced by both the presence of a tumor and lymphangiogenic normalization, while both angiogenic and lymphangiogenic normalization restored patterns of immune cell access to passively draining species. As a whole, this work uncovers the potential ramifications of tumor-induced angiogenesis and lymphangiogenesis, along with impacts of interrogation into these pathways, on access of tumor-derived species to immune cells. Impact Statement Angiogenic and lymphangiogenic normalization strategies have been utilized clinically to interrogate tumor vasculature with some success. In the age of immunotherapy, the impacts of these therapeutic interventions on immune remodeling are unclear. This work utilizes mouse models of angiogenic and lymphangiogenic normalization, along with a system of fluorescently tagged tracers, to uncover the impacts of angiogenesis and lymphangiogenesis on access of tumor-derived species to immune cell subsets within various organs.
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Affiliation(s)
- Meghan J. O'Melia
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA
| | - Nathan A. Rohner
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Susan Napier Thomas
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA
- George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
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17
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Papaconstantinou D, Tsilimigras DI, Pawlik TM. Recurrent Hepatocellular Carcinoma: Patterns, Detection, Staging and Treatment. J Hepatocell Carcinoma 2022; 9:947-957. [PMID: 36090786 PMCID: PMC9450909 DOI: 10.2147/jhc.s342266] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 08/29/2022] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide with the incidence of recurrence being as high as 88% even among patients who have undergone curative-intent treatment. Despite improvements in overall survival, recurrence remains a challenge necessitating accurate reappraisal of patient and disease status. To that end, accurate staging of recurrent HCC is a necessity to provide better care for these patients. Risk factors for poor survival after HCC recurrence have been identified and include characteristics of the primary disease, such as tumor multifocality, large size (≥5 cm), macroscopic vascular or microscopic lymphovascular invasion, preoperative a-fetoprotein (AFP) levels, R0 resection, and the presence of impaired liver function. Close surveillance with imaging is warranted following curative-intent therapy, with magnetic resonance imaging (MRI) being the preferred approach to identify small, early recurrent HCCs. Treatment decisions at the time of recurrence involve ruling out extrahepatic disease and identifying candidates for potentially curative-intent repeat treatment options. Patients with recurrent disease are, however, very diverse in terms of tumor morphology and biologic behavior, as well as residual hepatic functional reserve. Patients with preserved liver function may benefit from repeat liver resection or ablation. Patients with recurrence within the Milan criteria may even be candidates for salvage liver transplantation, while multimodality treatment with combination of liver-directed therapies appears to enhance oncologic outcomes for individuals with advanced recurrent disease. A “one-size-fits-all” approach in staging recurrent HCC does not exist. Rather, individualized and evidence-based decision-making is necessary in order to optimize outcomes for patients with recurrent HCC.
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Affiliation(s)
- Dimitrios Papaconstantinou
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Diamantis I Tsilimigras
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, Ohio, USA
| | - Timothy M Pawlik
- Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, Ohio, USA
- Correspondence: Timothy M Pawlik, Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University, Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH, USA, Tel +1 614 293 8701, Fax +1 614 293 4063, Email
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Fornaro L, Musettini G, Orlandi P, Pecora I, Vivaldi C, Banchi M, Salani F, Fini E, Massa V, Catanese S, Cucchiara F, Lencioni M, Masi G, Vasile E, Bocci G. Early increase of plasma soluble VEGFR-2 is associated with clinical benefit from second-line treatment of paclitaxel and ramucirumab in advanced gastric cancer. Am J Cancer Res 2022; 12:3347-3356. [PMID: 35968330 PMCID: PMC9360220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/08/2022] [Indexed: 06/15/2023] Open
Abstract
Ramucirumab plus paclitaxel is considered the standard of care in the second-line treatment of gastric carcinoma (GC). The aim of this study was to evaluate plasma vascular endothelial growth factor-A (VEGF-A), VEGF-D, and circulating soluble VEGF receptor-2 (sVEGFR-2) as possible markers of resistance or response to ramucirumab administered with paclitaxel in pretreated metastatic GC patients. Plasma samples were collected at different time points (on days 1 and 15 of the first 3 cycles, at best radiologic response and at disease progression). VEGF-A, VEGF-D and sVEGFR-2 were analysed by ELISA. Correlations of biomarker baseline levels or dynamic changes with outcome measures were assessed. Progression-free survival (PFS) was the primary endpoint of the study. Forty-one patients were enrolled. VEGF-A and VEGF-D, but not sVEGFR-2, values significantly increased during treatment compared to baseline (P < 0.001). A positive correlation between VEGF-A and sVEGFR-2 at cycle 2 was found (P=0.045). At univariate analysis, higher baseline levels of VEGF-A were associated with worse OS (P=0.015). Early increase of sVEGFR-2 levels after the first treatment cycle was the only factor associated with longer PFS (6.6 vs. 3.6 months, P=0.049) and OS (18.6 vs. 5.2 months, P=0.008). Significance of sVEGFR-2 early increase was retained at multivariate analysis for OS (HR 0.32; 95% CI 0.12-0.91; P=0.032). The reported results confirmed the prognostic role of baseline VEGF-A and, with the limitations of the limited sample size and the lack of a control arm, suggested that the early increase of sVEGFR-2 after 1 cycle of treatment could be a potential predictive biomarker of benefit from second-line ramucirumab plus paclitaxel in GC.
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Affiliation(s)
- Lorenzo Fornaro
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria PisanaPisa, Italy
| | - Gianna Musettini
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria PisanaPisa, Italy
- Unit of Medical Oncology, Ospedale di LivornoLivorno, Italy
| | - Paola Orlandi
- Department of Clinical and Experimental Medicine, University of PisaPisa, Italy
| | - Irene Pecora
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria PisanaPisa, Italy
- Unit of Medical Oncology, Ospedale della MisericordiaGrosseto, Italy
| | - Caterina Vivaldi
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria PisanaPisa, Italy
- Department of Translational Research and New Technologies in Medicine, University of PisaPisa, Italy
| | - Marta Banchi
- Department of Clinical and Experimental Medicine, University of PisaPisa, Italy
| | - Francesca Salani
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria PisanaPisa, Italy
| | - Elisabetta Fini
- Department of Clinical and Experimental Medicine, University of PisaPisa, Italy
| | - Valentina Massa
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria PisanaPisa, Italy
| | - Silvia Catanese
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria PisanaPisa, Italy
| | - Federico Cucchiara
- Department of Clinical and Experimental Medicine, University of PisaPisa, Italy
| | - Monica Lencioni
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria PisanaPisa, Italy
| | - Gianluca Masi
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria PisanaPisa, Italy
- Department of Translational Research and New Technologies in Medicine, University of PisaPisa, Italy
| | - Enrico Vasile
- Unit of Medical Oncology, Azienda Ospedaliero-Universitaria PisanaPisa, Italy
| | - Guido Bocci
- Department of Clinical and Experimental Medicine, University of PisaPisa, Italy
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19
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Kang SM, Khalil L, El-Rayes BF, Akce M. Rapidly Evolving Landscape and Future Horizons in Hepatocellular Carcinoma in the Era of Immuno-Oncology. Front Oncol 2022; 12:821903. [PMID: 35433430 PMCID: PMC9008732 DOI: 10.3389/fonc.2022.821903] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/08/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a serious global health problem as one of the leading causes of cancer-related death worldwide. Systemic therapy for advanced HCC has progressed with the development of molecular targeted agents, however survival benefits remain modest. More recently, immune checkpoint inhibitors (ICI) have emerged and exhibited promising therapeutic benefits in a subset of patients. Physiologically, the intrinsic microenvironment in the liver is immunosuppressive, which represents a major obstacle for effective immune therapies in primary and secondary liver malignancies. For this reason, combination therapies that can overcome immune inhibitory mechanisms and enhance the immune response are a rationale approach for drug development in HCC. A recent example is the combination of the anti-PD-L1 antibody (atezolizumab) and anti-VEGF-A antibody (bevacizumab), which has shown significant improvement in survival as compared to standard of care in the first-line treatment for HCC. Other immunotherapy approaches including cancer vaccines and adoptive cell therapy are also under investigation. This review summarizes the key trials leading to our current HCC treatment options and provides an overview of future immune-based strategies in development.
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Affiliation(s)
| | | | | | - Mehmet Akce
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, United States
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20
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Chen S, Li X, Wang H, Chen G, Zhou Y. Anti-VEGFR2 monoclonal antibody(MSB0254) inhibits angiogenesis and tumor growth by blocking the signaling pathway mediated by VEGFR2 in glioblastoma. Biochem Biophys Res Commun 2022; 604:158-164. [PMID: 35305420 DOI: 10.1016/j.bbrc.2022.03.045] [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: 03/02/2022] [Accepted: 03/08/2022] [Indexed: 11/30/2022]
Abstract
Angiogenesis is a key physiological process that plays a key role in glioblastoma (GBM) progression and displays therapeutic resistance to antiangiogenic therapies. In this study, we aimed to identify whether vascular endothelial growth factor receptor 2(VEGFR2)monoclonal antibodies(mab)could inhibit tumorigenicity and the formation of vascular mimicry (VM) in GBM. The bioinformatic analysis from TCGA, CGGA, and TCPA databases and Immunohistochemistry (IHC) revealed that VEGFR2 is highly expressed in glioma tissues and results in a poor prognosis and is positively associated with VM markers (CD34 and PAS). The anti-VEGFR2 monoclonal antibodies(MSB0254)could inhibit the invasion, migration, and VM formation of U251 and primary glioma cells in vitro. In vivo, MSB0254 (m) could not only inhibit the growth of transplanted tumors of U251 and GL261 cells, but also significantly inhibit the expression of CD34, VEGFR2, Ki67, MMP2, MMP9 and reduce the expression of CD34/PAS and inhibit VM formation. The VEGFR2 monoclonal antibody could inhibit the angiogenesis and tumor growth of GBM by blocking the signaling pathway mediated by VEGFR2. It may become a new supplementary treatment for GBM.
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Affiliation(s)
- Sansong Chen
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, 215000, Jiangsu Province, China; Department of Neurosurgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), No.2 Zheshan Road, Wuhu, 241001, Anhui Province, China
| | - Xuetao Li
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, 215000, Jiangsu Province, China
| | - Hao Wang
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, 215000, Jiangsu Province, China
| | - Guangliang Chen
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, 215000, Jiangsu Province, China
| | - Youxin Zhou
- Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou, 215000, Jiangsu Province, China.
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21
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Yen CC, Yen CJ. Safety of ramucirumab treatment in patients with advanced hepatocellular carcinoma and elevated alpha-fetoprotein. Expert Opin Drug Saf 2022; 21:157-166. [PMID: 34668832 DOI: 10.1080/14740338.2022.1995353] [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: 02/17/2021] [Accepted: 10/15/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is the second most common cause of cancer-induced deaths worldwide, and limited therapeutic options are available for patients with advanced disease. Ramucirumab, a monoclonal antibody that blocks the vascular endothelial growth factor (VEGF) receptor-2, is the first biomarker-selected systemic agent with therapeutic efficacy, tolerability, and favorable patient-reported outcomes in patients with advanced HCC and elevated serum α-fetoprotein levels ≥400 ng/mL, who are resistant or intolerant to sorafenib therapy. However, treatment-induced adverse events (AEs), such as hypertension, proteinuria, bleeding, thromboembolism, and gastrointestinal perforation remain challenging and potentially fatal concerns. AREAS COVERED This review discusses the published or ongoing studies and subgroup analyses on ramucirumab therapy in patients with advanced HCC. We present information on the risks of ramucirumab-induced common or rare AEs and their management. EXPERT OPINION Ramucirumab toxicity secondary to VEGF inhibition is similar to the AEs that are known to be associated with other VEGF-blocking antibodies. Common AEs can be safely treated using conventional measures; however, rare and potentially fatal AEs necessitate close monitoring. With regard to the safety profile, more promising ramucirumab-containing combination therapies are likely to pave the future path for effective HCC treatment.
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Affiliation(s)
- Chih-Chieh Yen
- Division of Hematology/ Oncology, Department of Internal Medicine, National Cheng Kung University Hospital Douliou Branch, Yunlin, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Jui Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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22
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Precision Medicine for Hepatocellular Carcinoma: Clinical Perspective. J Pers Med 2022; 12:jpm12020149. [PMID: 35207638 PMCID: PMC8879044 DOI: 10.3390/jpm12020149] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major malignant diseases worldwide, characterized by growing incidence and high mortality rates despite apparent improvements in surveillance programs, diagnostic and treatment procedures, molecular therapies, and numerous research initiatives. Most HCCs occur in patients with liver cirrhosis, and the competing mortality risks from the tumor and the cirrhosis should be considered. Presently, previously identified risk factors, such as hepatitis virus infection, hepatic inflammation and fibrosis, and metabolic syndrome, may be used as chemoprevention targets. The application of precision medicine for HCC management challenges the one-size-fits-all concept; moreover, patients should no longer be treated entirely according to the histology of their tumor but based on molecular targets specific to their tumor biology. Next-generation sequencing emphasizes HCC molecular heterogeneity and aids our comprehension of possible vulnerabilities that can be exploited. Moreover, genetic sequencing as part of a precision medicine concept may work as a promising tool for postoperative cancer monitoring. The use of genetic and epigenetic markers to identify therapeutic vulnerability could change the diagnosis and treatment of HCC, which so far was based on Barcelona clinic liver cancer (BCLC) staging. In daily clinical practice, the shift from a stage-oriented to a therapeutic-oriented approach is needed to direct the choice of HCC treatment toward the potentially most effective option on an individual basis. The important factor in precision medicine is the promotion of patient management based on the individual approach, knowing that the final decision must be approved by a multidisciplinary expert team.
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23
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Choucair K, Kamran S, Saeed A. Clinical Evaluation of Ramucirumab for the Treatment of Hepatocellular Carcinoma (HCC): Place in Therapy. Onco Targets Ther 2022; 14:5521-5532. [PMID: 35002257 PMCID: PMC8721285 DOI: 10.2147/ott.s268309] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 12/21/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma remains one of the leading causes of death from cancer worldwide as most cases are diagnosed at an advanced disease stage. Ramucirumab, a human anti-VEGFR-2 monoclonal antibody, is approved as a monotherapy for the treatment of patients with hepatocellular carcinoma and α-fetoprotein levels ≥400 ng/mL previously treated with sorafenib. As most patients present with an advanced disease, patients with α-fetoprotein levels ≥400 ng/mL have an aggressive disease and a poor prognosis, making ramucirumab an important treatment option for this subgroup of patients. This article provides a comprehensive review of the clinical efficacy of ramucirumab as highlighted in the two major trials that lead to its approval. We also briefly review the agent pharmacologic properties, as well as its safety and toxicity profile, before discussing certain limitations and challenges associated with ramucirumab use. Finally, we review completed and ongoing clinical trials and focus on those involving ramucirumab-based combinations, namely with immune therapy.
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Affiliation(s)
- Khalil Choucair
- Department of Medicine, Kansas University School of Medicine, Wichita, KS, USA
| | - Syed Kamran
- Department of Medicine, Kansas University School of Medicine, Wichita, KS, USA
| | - Anwaar Saeed
- Department of Medicine, Division of Medical Oncology, Kansas University Cancer Center, Kansas City, KS, USA
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24
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Zhang H, Zhang W, Jiang L, Chen Y. Recent advances in systemic therapy for hepatocellular carcinoma. Biomark Res 2022; 10:3. [PMID: 35000616 PMCID: PMC8744248 DOI: 10.1186/s40364-021-00350-4] [Citation(s) in RCA: 135] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 09/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors in the world. Therapeutic options for advanced HCC are limited. Systemic treatment, especially with conventional cytotoxic drugs, is usually ineffective. For more than a decade, sorafenib has been the only systemic drug that has been proven to be clinically effective for treating advanced HCC. However, over the past three years, the rapid progress of molecular targeted therapies has dramatically changed the treatment landscape for advanced HCC. Immune checkpoint therapies are now being incorporated into HCC therapies, and their combination with molecular targeted therapy is emerging as a tool to enhance the immune response. In this review, we summarize the development and progress of molecular targeted agents and immunotherapies in HCC.
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Affiliation(s)
- Huajun Zhang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Wuyang Zhang
- Clinical skills training center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Longying Jiang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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25
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Pathak S, Sonbol MB. Second-Line Treatment Options for Hepatocellular Carcinoma: Current Landscape and Future Direction. J Hepatocell Carcinoma 2021; 8:1147-1158. [PMID: 34584898 PMCID: PMC8464222 DOI: 10.2147/jhc.s268314] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/31/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma is a leading cause of mortality worldwide, and its incidence is rising. The last few years have witnessed a proliferation of available systemic therapeutic options, with the approval of multiple agents, including immune checkpoint inhibitors and drugs targeting vascular endothelial growth factor, such as cabozantinib, regorafenib, and ramucirumab. Most recently, the combination of atezolizumab plus bevacizumab has resulted in the longest overall survival yet known in hepatocellular carcinoma, therefore changing the preferred first-line treatment from the previous options of sorafenib and lenvatinib. The aim of this review is to summarize the available clinical data for the current second-line systemic treatment options and the future perspectives in the treatment landscape of hepatocellular carcinoma.
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Affiliation(s)
- Surabhi Pathak
- Hematology-Oncology, King’s Daughters Medical Center, Ashland, KY, USA
| | - Mohamad Bassam Sonbol
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Cancer Center, Phoenix, AZ, USA
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26
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Niu M, Yi M, Li N, Wu K, Wu K. Advances of Targeted Therapy for Hepatocellular Carcinoma. Front Oncol 2021; 11:719896. [PMID: 34381735 PMCID: PMC8350567 DOI: 10.3389/fonc.2021.719896] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 07/12/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the common and fatal malignancies, which is a significant global health problem. The clinical applicability of traditional surgery and other locoregional therapies is limited, and these therapeutic strategies are far from satisfactory in improving the outcomes of advanced HCC. In the past decade, targeted therapy had made a ground-breaking progress in advanced HCC. Those targeted therapies exert antitumor effects through specific signals, including anti-angiogenesis or cell cycle progression. As a standard systemic therapy option, it tremendously improves the survival of this devastating disease. Moreover, the combination of targeted therapy with immune checkpoint inhibitor (ICI) has demonstrated more potent anticancer effects and becomes the hot topic in clinical studies. The combining medications bring about a paradigm shift in the treatment of advanced HCC. In this review, we presented all approved targeted agents for advanced HCC with an emphasis on their clinical efficacy, summarized the advances of multi-target drugs in research for HCC and potential therapeutic targets for drug development. We also discussed the exciting results of the combination between targeted therapy and ICI.
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Affiliation(s)
- Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ning Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Kongju Wu
- Department of Nursing, Medical School of Pingdingshan University, Pingdingshan, China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
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Molecularly targeted therapy for advanced gastrointestinal noncolorectal cancer treatment: how to choose? Past, present, future. Anticancer Drugs 2021; 32:593-601. [PMID: 33929995 DOI: 10.1097/cad.0000000000001071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Gastrointestinal cancer is a leading cause of death worldwide. Conventional cytotoxic chemotherapy has been the backbone of advanced gastrointestinal cancer treatment for decades and still represents a key element of the therapeutic armamentarium. However, only small increments in survival outcomes have been reached. New clinical trials are designed, including classic chemotherapy in association with either small-molecule inhibitors or mAb. During the past few years, remarkable progress in molecular biology of gastrointestinal noncolorectal cancers, the discovery of specific targets and the resulting development of systemic drugs that block critical kinases and several molecular pathways have all contributed to progress. New biological agents with molecularly targeted therapies are now available or currently included in clinical trials (EGFR inhibitors (i), antiangiogenic agents, c-METi, IDHi, FGFR2i, BRAFi, Pi3Ki/AKTi/mTORi, NTRKi). When we focus on the current state of precision medicine for gastrointestinal malignancies, it becomes apparent that there is a mixed history of success and failure. The aim of this review is to focus on the studies that have been completed to date with target therapies and to understand which of these are currently the accepted choice in clinical practice and which need further confirmation and approval for inclusion in guidelines. All these findings will enable to guide clinical practice for oncologists in the design of the next round of clinical trials.
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28
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Liver Cancer: Therapeutic Challenges and the Importance of Experimental Models. Can J Gastroenterol Hepatol 2021; 2021:8837811. [PMID: 33728291 PMCID: PMC7937489 DOI: 10.1155/2021/8837811] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 01/16/2021] [Accepted: 02/16/2021] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is one of the main causes of death related to cancer worldwide; its etiology is related with infections by C or B hepatitis virus, alcohol consumption, smoking, obesity, nonalcoholic fatty liver disease, diabetes, and iron overload, among other causes. Several kinds of primary liver cancer occur, but we will focus on hepatocellular carcinoma (HCC). Numerous cellular signaling pathways are implicated in hepatocarcinogenesis, including YAP-HIPPO, Wnt-β-catenin, and nuclear factor-κB (NF-κB); these in turn are considered novel therapeutic targets. In this review, the role of lipid metabolism regulated by peroxisome proliferator-activated receptor gamma (PPARγ) in the development of HCC will also be discussed. Moreover, recent evidence has been obtained regarding the participation of epigenetic changes such as acetylation and methylation of histones and DNA methylation in the development of HCC. In this review, we provide detailed and current information about these topics. Experimental models represent useful tools for studying the different stages of liver cancer and help to develop new pharmacologic treatments. Each model in vivo and in vitro has several characteristics and advantages to offer for the study of this disease. Finally, the main therapies approved for the treatment of HCC patients, first- and second-line therapies, are described in this review. We also describe a novel option, pirfenidone, which due to its pharmacological properties could be considered in the future as a therapeutic option for HCC treatment.
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Vacchelli E, Aranda F, Eggermont A, Galon J, Sautès-Fridman C, Zitvogel L, Kroemer G, Galluzzi L. Trial Watch: Tumor-targeting monoclonal antibodies in cancer therapy. Oncoimmunology 2021; 3:e27048. [PMID: 24605265 PMCID: PMC3937194 DOI: 10.4161/onci.27048] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Accepted: 11/01/2013] [Indexed: 02/06/2023] Open
Abstract
In 1997, for the first time in history, a monoclonal antibody (mAb), i.e., the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug Administration for use in cancer patients. Since then, the panel of mAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has not stopped to expand, nowadays encompassing a stunning amount of 15 distinct molecules. This therapeutic armamentarium includes mAbs that target tumor-associated antigens, as well as molecules that interfere with tumor-stroma interactions or exert direct immunostimulatory effects. These three classes of mAbs exert antineoplastic activity via distinct mechanisms, which may or may not involve immune effectors other than the mAbs themselves. In previous issues of OncoImmunology, we provided a brief scientific background to the use of mAbs, all types confounded, in cancer therapy, and discussed the results of recent clinical trials investigating the safety and efficacy of this approach. Here, we focus on mAbs that primarily target malignant cells or their interactions with stromal components, as opposed to mAbs that mediate antineoplastic effects by activating the immune system. In particular, we discuss relevant clinical findings that have been published during the last 13 months as well as clinical trials that have been launched in the same period to investigate the therapeutic profile of hitherto investigational tumor-targeting mAbs.
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Affiliation(s)
- Erika Vacchelli
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France ; Université Paris-Sud/Paris XI; Paris, France
| | - Fernando Aranda
- Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France
| | | | - Jérôme Galon
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, U872; Paris, France ; Equipe 15, Centre de Recherche des Cordeliers; Paris, France
| | - Catherine Sautès-Fridman
- Université Pierre et Marie Curie/Paris VI; Paris, France ; INSERM, U872; Paris, France ; Equipe 13, Centre de Recherche des Cordeliers; Paris, France
| | - Laurence Zitvogel
- Gustave Roussy; Villejuif, France ; INSERM, U1015; CICBT507; Villejuif, France
| | - Guido Kroemer
- Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP; Paris, France ; Metabolomics and Cell Biology Platforms; Gustave Roussy; Villejuif, France ; INSERM, U848; Villejuif, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France ; Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France
| | - Lorenzo Galluzzi
- Gustave Roussy; Villejuif, France ; Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Equipe 11 labellisée par la Ligue Nationale contre le Cancer; Centre de Recherche des Cordeliers; Paris, France
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Cersosimo RJ. Systemic targeted and immunotherapy for advanced hepatocellular carcinoma. Am J Health Syst Pharm 2021; 78:187-202. [PMID: 33211092 DOI: 10.1093/ajhp/zxaa365] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
PURPOSE The activity of targeted agents and immunotherapy in the management of advanced hepatocellular carcinoma (HCC) is reviewed. SUMMARY The first drug approved by the Food and Drug Administration for advanced HCC, sorafenib, was approved in 2007. Regorafenib, the second drug, was approved 10 years later. Six additional drugs have been approved since. Targeted agents and checkpoint inhibitors are the only agents approved for systemic therapy of advanced HCC. Sorafenib and lenvatinib are approved as first-line agents, with regorafenib, cabozantinib, ramucirumab, nivolumab (used alone or with ipilimumab), and pembrolizumab approved for patients who have received prior sorafenib therapy. Most patients in phase 3 studies had Child-Pugh class A cirrhosis, and data on the use of these agents in patients with more advanced hepatic dysfunction are limited. All of the targeted agents improve survival in patients with advanced disease. Median overall survival durations of up to 12.3 and 13.6 months were reported with use of sorafenib and lenvatinib, respectively, in phase 3 trials. Overall survival durations of 10.6, 10.2, and 9.2 months have been achieved with use of regorafenib, cabozantinib, and ramucirumab as second-line therapy after sorafenib. A median overall survival of 13.2 months was reported in 1 cohort of a dose-expansion study of nivolumab in which all patients received prior sorafenib therapy. Median survival durations of 12.9 months and 13.9 months were reported with use of pembrolizumab in patients with a history of sorafenib therapy. The most common adverse effects associated with targeted agents are dermatological effects, diarrhea, fatigue, and hypertension. Immune-mediated adverse effects are associated with checkpoint inhibitors. CONCLUSION Targeted agents and checkpoint inhibitors are the standard of therapy for patients who need systemic therapy for advanced HCC.
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Affiliation(s)
- Robert J Cersosimo
- School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA, and Veterans Affairs Medical Center, Boston, MA
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Hatanaka T, Naganuma A, Shibasaki M, Kohga T, Arai Y, Nagashima T, Ueno T, Namikawa M, Saito S, Hoshino T, Takizawa D, Arai H, Makita F, Kakizaki S, Harimoto N, Shirabe K, Uraoka T. The Role of the Albumin-Bilirubin Score for Predicting the Outcomes in Japanese Patients with Advanced Hepatocellular Carcinoma Treated with Ramucirumab: A Real-World Study. Oncology 2020; 99:203-214. [PMID: 33279908 DOI: 10.1159/000511734] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 09/21/2020] [Indexed: 01/27/2023]
Abstract
AIM The aim of this retrospective study was to investigate the efficacy and safety of ramucirumab treatment under real-world conditions and to clarify the role of albumin-bilirubin (ALBI) score in predicting outcomes. METHODS Between June 2019 and May 2020, a total of 16 patients with advanced hepatocellular carcinoma (HCC) treated with ramucirumab in Gunma Saiseikai Maebashi Hospital and its affiliated hospitals was included. RESULTS The median age was 71 (interquartile range [IQR] 65-74) years old, and 12 patients (75.0%) were male. The modified ALBI (mALBI) grade was 1, 2a, and 2b at baseline in 4 (25.0%), 3 (18.8%), and 9 patients (56.3%), respectively. The Barcelona Clinic Liver Cancer stage was intermediate and advanced stage in 1 (6.3%) and 15 patients (93.8%), respectively. The serum α-fetoprotein at baseline was 4,911 (IQR 2,091-17,377) ng/mL. The disease control rate in patients with mALBI grade1 + 2a was significantly higher than in those with mALBI grade 2b (100 vs. 28.6%, p = 0.028). The patients with mALBI grade 1 + 2a had a significantly better overall survival (OS) and longer progression-free survival (PFS) than those with mALBI grade 2b (median OS 6.7 vs. 3.0 months; p = 0.036, median PFS 7.5 vs. 1.4 months; p = 0.002). The number of cycles of ramucirumab treatment was significantly correlated with the ALBI score (r = -0.452, p = 0.030). The patients with mALBI grade 1 + 2a showed a low incidence of adverse events (AEs) and discontinuation due to AEs. CONCLUSIONS Advanced HCC patients with mALBI grade 1 + 2a may be a good indication for ramucirumab treatment.
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Affiliation(s)
- Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan,
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | | | - Tatsuya Kohga
- Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan
| | - Yosuke Arai
- Department of Internal Medicine, Kiryu Kosei General Hospital, Kiryu, Japan
| | - Tamon Nagashima
- Department of Gastroenterology, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan
| | - Takashi Ueno
- Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan
| | - Masashi Namikawa
- Department of Internal Medicine, Kiryu Kosei General Hospital, Kiryu, Japan
| | - Shuichi Saito
- Department of Gastroenterology, Tomioka General Hospital, Tomioka, Japan
| | - Takashi Hoshino
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Daichi Takizawa
- Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Japan
| | - Hirotaka Arai
- Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Japan
| | - Fujio Makita
- Department of Gastrointestinal Surgery, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Norifumi Harimoto
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Ken Shirabe
- Department of Hepatobiliary and Pancreatic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan
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32
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Kudo M, Galle PR, Brandi G, Kang YK, Yen CJ, Finn RS, Llovet JM, Assenat E, Merle P, Chan SL, Palmer DH, Ikeda M, Yamashita T, Vogel A, Huang YH, Abada PB, Yoshikawa R, Shinozaki K, Wang C, Widau RC, Zhu AX. Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2. JHEP Rep 2020; 3:100215. [PMID: 33392490 PMCID: PMC7772786 DOI: 10.1016/j.jhepr.2020.100215] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 10/06/2020] [Accepted: 10/19/2020] [Indexed: 02/08/2023] Open
Abstract
Background & Aims The albumin–bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this post hoc analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC. Methods Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle. Results Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 vs. 1; hazard ratio [HR]: 1.38 [1.13–1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445–0.824]) and ALBI grade 2 (HR 0.814 [0.630–1.051]). Conclusions Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade. Lay summary Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate ramucirumab did not impair liver function when compared with placebo.
In patients with HCC, the severity of coexisting liver dysfunction is usually categorised using the Child-Pugh system. We demonstrate that the simpler albumin–bilirubin (ALBI) nomogram can be used for pre-treatment prognostication and on-treatment assessment. Ramucirumab did not negatively impact on liver function compared to placebo in patients with advanced HCC and elevated AFP. Liver-specific adverse events were reported more frequently in patients with more severe liver disfunction at baseline. Ramucirumab provided a survival benefit irrespective of baseline liver function in patients with advanced HCC and elevated AFP.
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Key Words
- AE, adverse event
- AESI, adverse event of special interest
- AFP, alpha-fetoprotein
- ALBI
- ALBI, albumin–bilirubin
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- BCLC, Barcelona Clinic Liver Cancer
- BOR, best overall response
- BSC, best supportive care
- CP, Child-Pugh
- CR, complete response
- ECOG PS, Eastern Cooperative Oncology Group performance status
- EoT, end of treatment
- GGT, gamma-glutamyltransferase
- HCC, hepatocellular carcinoma
- HR, hazard ratio
- IQR, inter-quartile range
- ITT, intent-to-treat
- Liver function
- MVI, macrovascular invasion
- OS, overall survival
- PD, progressive disease
- PR, partial response
- Prognosis
- Ram, ramucirumab
- SD, stable disease
- Safety
- Survival
- TACE, transarterial chemoembolisation
- Tumour response
- VEGF, vascular endothelial growth factor
- VEGFRs, vascular endothelial growth factor receptors
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University, Osaka-Sayama, Japan
| | - Peter R Galle
- Medizinische Klinik und Poliklinik, University Medical Center, Mainz, Germany
| | - Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, Saint Orsola Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea
| | - Chia-Jui Yen
- Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Richard S Finn
- Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Josep M Llovet
- Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Institut d´Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
| | - Eric Assenat
- Département d'oncologie médicale, CHU de Montpellier, Montpellier, France
| | - Philippe Merle
- Hepatology and Gastroenterology Unit, Hôpital de la Croix Rousse, Lyon, France
| | - Stephen L Chan
- State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, Hong Kong, People's Republic of China.,Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, People's Republic of China
| | - Daniel H Palmer
- Molecular and Clinical Cancer Medicine, Clatterbridge Cancer Centre, University of Liverpool, Bebington, Wirral, UK
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Ishikawa, Japan
| | - Arndt Vogel
- Klinik für Gastroenterologie, Hepatologie and Endokrinologie, Hannover Medical School, Hannover, Germany
| | - Yi-Hsiang Huang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | | | | | | | | | - Ryan C Widau
- Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical Center, Boston, MA, USA
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Winters AC, Bedier F, Saab S. Management of Side Effects of Systemic Therapies for Hepatocellular Carcinoma: Guide for the Hepatologist. Clin Liver Dis 2020; 24:755-769. [PMID: 33012457 DOI: 10.1016/j.cld.2020.07.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Historically, systemic treatment of advanced hepatocellular carcinoma was limited to the tyrosine kinase inhibitor sorafenib. With the recent approval of several new agents the armamentarium of treatment options available to providers and patients has expanded. Although these promising advances offer hope for patients with advanced hepatocellular carcinoma, they also present new and challenging adverse effects that threaten to limit their efficacy. Immunotherapy with checkpoint inhibitors introduce immune-related adverse events, which may affect a wide array of organ systems. With prompt recognition, however, common side effects of systemic therapies for hepatocellular carcinoma are predictable, manageable, and many improve with appropriate intervention.
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Affiliation(s)
- Adam C Winters
- Pfleger Liver Institute, 200 Medical Plaza Driveway, Suite 214, Los Angeles, CA 90095, USA
| | - Fatima Bedier
- Pfleger Liver Institute, 200 Medical Plaza Driveway, Suite 214, Los Angeles, CA 90095, USA
| | - Sammy Saab
- Pfleger Liver Institute, 200 Medical Plaza Driveway, Suite 214, Los Angeles, CA 90095, USA.
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Yen CJ, Kudo M, Lim HY, Hsu CH, Vogel A, Brandi G, Cheng R, Nitu IS, Abada P, Hsu Y, Zhu AX, Kang YK. Efficacy and Safety of Ramucirumab in Asian and Non-Asian Patients with Advanced Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: Pooled Individual Data Analysis of Two Randomized Studies. Liver Cancer 2020; 9:440-454. [PMID: 32999870 PMCID: PMC7506228 DOI: 10.1159/000506946] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 02/29/2020] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE REACH-2 and REACH were randomized, placebo-controlled, double-blind, multicenter phase 3 trials which showed survival benefits of ramucirumab treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP). We evaluated the efficacy and safety of ramucirumab in Asian and non-Asian patients with AFP ≥400 ng/mL from REACH-2 and REACH. METHODS We pooled Asian and non-Asian patients from the REACH-2 and REACH trials and performed an individual patient data meta-analysis. Overall survival (OS) and progression-free survival were evaluated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated with a stratified Cox regression model. RESULTS In the pooled REACH-2 and REACH patient population, 291 Asian patients were randomly assigned to receive ramucirumab (n = 168) or placebo (n = 123), and 251 non-Asian patients received ramucirumab (n = 148) or placebo (n = 103). The median OS was significantly longer in the ramucirumab arm in comparison to the placebo arm for Asian patients (8.08 vs. 4.76 months, stratified HR 0.73 [95% CI 0.56-0.95], p = 0.0189) and non-Asian patients (7.98 vs. 5.22 months, stratified HR 0.65 [95% CI 0.49-0.86], p = 0.0028). The overall response rate (ORR) and disease control rate (DCR) were significantly higher in the ramucirumab arm compared to the placebo arm for Asian patients (ORR: 4.2 vs. 0.8%; DCR: 53.6 vs. 33.3%) and non-Asian patients (ORR: 6.8 vs. 1.0%; DCR: 59.5 vs. 41.7%). The most common grade ≥3 treatment-emergent adverse events reported in the ramucirumab arm were hypertension (7.7%), decreased appetite (1.2%), and ascites (1.2%) for Asian patients and hypertension (16.9%), ascites (8.8%), asthenia (4.7%), and fatigue (5.4%) for non-Asian patients. DISCUSSION AND CONCLUSION This pooled analysis of the REACH-2/REACH trials demonstrates significant benefits, with a manageable safety profile, of ramucirumab treatment in Asian and non-Asian patients with advanced HCC and baseline AFP ≥400 ng/mL.
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Affiliation(s)
- Chia-Jui Yen
- Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Ho-Yeong Lim
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Chih-Hung Hsu
- National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan
| | | | - Giovanni Brandi
- Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | | | | | - Paolo Abada
- Eli Lilly and Company, Indianapolis, Indiana, USA
| | - Yanzhi Hsu
- TG Therapeutics Inc., New York, New York, USA
| | - Andrew X. Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Yoon-Koo Kang
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea,*Yoon-Koo Kang, MD, PhD, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505 (South Korea),
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De Luca E, Marino D, Di Maio M. Ramucirumab, A Second-Line Option For Patients With Hepatocellular Carcinoma: A Review Of The Evidence. Cancer Manag Res 2020; 12:3721-3729. [PMID: 32547208 PMCID: PMC7246316 DOI: 10.2147/cmar.s216220] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 04/27/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and predominantly develops in patients with liver cirrhosis. In patients with advanced disease, such as extra-hepatic extension or portal vein involvement, and with intermediate disease unsuitable for locoregional therapies, systemic therapy is recommended, if liver function and performance status are adequate. Following a decade of negative Phase III trials since the approval of sorafenib, more recently several drugs have proven efficacy both in first line versus sorafenib (lenvatinib) or in second line versus placebo (regorafenib, cabozantinib, ramucirumab). In this review, we summarize the preclinical and clinical evidence supporting the use of ramucirumab, a recombinant IgG1 monoclonal antibody that specifically binds to Vascular Endothelial Growth Factor receptor 2 (VEGFR-2), in HCC. Following the results of the REACH trial, that was negative in the overall study population but identified a subgroup that could benefit from ramucirumab treatment, the REACH-2 trial was a randomized, placebo-controlled trial, designed to assess ramucirumab as second line in patients with alpha-fetoprotein (AFP) ≥400 ng/mL. The results of REACH-2 were published in February 2019, leading to Food and Drug Administration and European Medicines Agency approval of the drug as second-line agent for advanced HCC (after sorafenib) in patients with AFP ≥400 ng/mL. For the first time in the history of systemic treatments for HCC, a predictive factor of efficacy was identified. In this review, we also discuss the potential clinical development of systemic treatments in HCC, focusing on combination therapies with immunotherapy (following the recent results of the combination of atezolizumab and bevacizumab in the IMbrave 150 clinical trial) and treatment sequences as a way to maximize survival benefit.
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Affiliation(s)
- Emmanuele De Luca
- Department of Oncology, University of Turin, Torino, Italy.,Division of Medical Oncology, Ordine Mauriziano Hospital, Torino, Italy
| | - Donatella Marino
- Department of Oncology, University of Turin, Torino, Italy.,Division of Medical Oncology, Ordine Mauriziano Hospital, Torino, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Torino, Italy.,Division of Medical Oncology, Ordine Mauriziano Hospital, Torino, Italy
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Pasquier J, Ghiabi P, Chouchane L, Razzouk K, Rafii S, Rafii A. Angiocrine endothelium: from physiology to cancer. J Transl Med 2020; 18:52. [PMID: 32014047 PMCID: PMC6998193 DOI: 10.1186/s12967-020-02244-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 01/28/2020] [Indexed: 02/08/2023] Open
Abstract
The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The significance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogenesis that is critical for tumor initiation and growth. Nevertheless, the identification of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profiling studies have demonstrated distinctive expression patterns in tumor-associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identified which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies.
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Affiliation(s)
- Jennifer Pasquier
- Nice Breast Institute, 57 bld de la Californie, 06000, Nice, France.
- Stem Cell & Microenvironment Laboratory, Weill Cornell Medicine-Qatar, Doha, Qatar.
| | - Pegah Ghiabi
- Stem Cell & Microenvironment Laboratory, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Lotfi Chouchane
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, 10065, USA
- Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Kais Razzouk
- Nice Breast Institute, 57 bld de la Californie, 06000, Nice, France
| | - Shahin Rafii
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Arash Rafii
- Nice Breast Institute, 57 bld de la Californie, 06000, Nice, France
- Stem Cell & Microenvironment Laboratory, Weill Cornell Medicine-Qatar, Doha, Qatar
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
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37
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Abstract
Ramucirumab (Cyramza®), a fully human anti-VEGFR-2 monoclonal antibody, has been approved as monotherapy for the treatment of patients with hepatocellular carcinoma (HCC) and α-fetoprotein levels ≥ 400 ng/mL who have been treated with sorafenib. Ramucirumab significantly prolonged overall survival (OS) and progression-free survival (PFS) relative to placebo in this population in the randomized, double-blind phase 3 REACH 2 trial. These benefits were seen in key prespecified subgroups based on demographic and disease characteristics. Ramucirumab had an acceptable tolerability profile and manageable safety profile in these patients, with the majority of treatment-related adverse events being mild or moderate in severity. The safety profile of ramucirumab was consistent with that expected for agents targeting the VEGF/VEGFR axis. Currently, ramucirumab is the only therapy specifically tested in patients with α-fetoprotein levels ≥ 400 ng/mL, which is associated with an aggressive disease and poor prognosis. Therefore, ramucirumab is an important treatment option for patients with HCC and α-fetoprotein levels ≥ 400 ng/mL who have been treated with sorafenib.
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Affiliation(s)
- Yahiya Y Syed
- Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
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38
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Galati G, Massimo Vainieri AF, Maria Fulgenzi CA, Di Donato S, Silletta M, Gallo P, Onorato A, Vespasiani-Gentilucci U, Picardi A. Current Treatment Options for HCC: From Pharmacokinetics to Efficacy and Adverse Events in Liver Cirrhosis. Curr Drug Metab 2020; 21:866-884. [PMID: 32957880 DOI: 10.2174/1389200221999200918141239] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 06/09/2020] [Accepted: 07/27/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is among the world's most common cancers. For over ten years, the only medical treatment for it has been the multikinase inhibitor Sorafenib. Currently, however, other first or second-line therapeutic options have also shown efficacy against HCC, such as multikinase inhibitors (Regorafenib, Lenvatinib, and Cabozantinib), a monoclonal antibody against the vascular endothelial growth factor receptor 2 (Ramucirumab), and immune-checkpoint inhibitors (Nivolumab, Pembrolizumab, Ipilimumab). AIM The aim of this paper is to review the metabolic pathways of drugs that have been tested for the treatment of HCC and the potential influence of liver failure over those pathways. METHODS The Food and Drug Administration (FDA)'s and European Medicines Agency (EMA)'s datasheets, results from clinical trials and observational studies have been reviewed. RESULTS This review summarizes the current knowledge regarding targets, metabolic pathways, drug interactions, and adverse events of medical treatments for HCC in cirrhotic patients. CONCLUSION The new scenario of systemic HCC therapy includes more active drugs with different metabolic pathways and different liver adverse events. Clinical and pharmacological studies providing more data on the safety of these molecules are urgently needed.
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Affiliation(s)
- Giovanni Galati
- Unit of Clinical Medicine and Hepatology, University Campus Bio-Medico, Rome, Italy
| | | | | | - Stefano Di Donato
- Unit of Clinical Medicine and Hepatology, University Campus Bio-Medico, Rome, Italy
| | | | - Paolo Gallo
- Unit of Clinical Medicine and Hepatology, University Campus Bio-Medico, Rome, Italy
| | - Angelo Onorato
- Medical Oncology Unit, University Campus Bio-Medico, Rome, Italy
| | | | - Antonio Picardi
- Unit of Clinical Medicine and Hepatology, University Campus Bio-Medico, Rome, Italy
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Abou-Alfa GK, Jarnagin W, El Dika I, D'Angelica M, Lowery M, Brown K, Ludwig E, Kemeny N, Covey A, Crane CH, Harding J, Shia J, O'Reilly EM. Liver and Bile Duct Cancer. ABELOFF'S CLINICAL ONCOLOGY 2020:1314-1341.e11. [DOI: 10.1016/b978-0-323-47674-4.00077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Roviello G, Sohbani N, Petrioli R, Rodriquenz MG. Ramucirumab as a second line therapy for advanced HCC: a significant achievement or a wasted opportunity for personalised therapy? Invest New Drugs 2019; 37:1274-1288. [PMID: 30879152 DOI: 10.1007/s10637-019-00760-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 03/08/2019] [Indexed: 02/08/2023]
Abstract
The second line treatment of hepatocellular carcinoma (HCC) has recently become an exciting area of interest since new emerging options have demonstrated survival benefits versus placebo. Unfortunately, predictive biomarkers are unavailable for these treatments. Ramucirumab, a monoclonal antibody against VEGFR-2, has demonstrated overall survival superiority against placebo as a second line therapy for patients with AFP > 400 ng/ml in the recent REACH-2 trial. This review will provide the current updated knowledge regarding the HCC cancerogenesis and angiogenic VEGF/VEGFR-2 pathways and the clinical development of ramucirumab in advanced HCC. This study will also critically assess the gaps in a previous negative phase III trial that tested other potentially useful treatments and suggest ways to modernise clinical trials and personalise therapy for advanced HCC.
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Affiliation(s)
- Giandomenico Roviello
- Department of Health Sciences, University of Florence, viale Pieraccini, 6, 50139, Florence, Italy.
| | - Navid Sohbani
- Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, 34129, Trieste, Italy
| | - Roberto Petrioli
- Medical Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Maria Grazia Rodriquenz
- Division of Medical Oncology, Department of Onco-Hematology, IRCCS-CROB, Referral Cancer Center of Basilicata, via Padre Pio 1, 85028, Rionero, Vulture, PZ, Italy
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Personeni N, Pressiani T, Bozzarelli S, Rimassa L. Targeted agents for second-line treatment of advanced hepatocellular carcinoma. World J Gastrointest Oncol 2019; 11:788-803. [PMID: 31662820 PMCID: PMC6815920 DOI: 10.4251/wjgo.v11.i10.788] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 07/25/2019] [Accepted: 08/28/2019] [Indexed: 02/05/2023] Open
Abstract
Over the past ten years, sorafenib, a multikinase inhibitor, has been the standard of care for patients with unresectable hepatocellular carcinoma (HCC) and well-preserved liver function. Recently, lenvatinib, a different multikinase inhibitor, was shown to be non-inferior to sorafenib, in terms of survival, while all other agents previously tested failed to prove non-inferiority (or superiority) when compared to sorafenib. Similarly, in the second-line setting, most investigational drugs failed to provide better survival outcomes than placebo. However, in the last 2 years three positive phase III trials have been published in this setting. The RESORCE trial, a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib, showed better outcomes with regorafenib compared to placebo. More recently, the phase III CELESTIAL trial demonstrated the superiority of cabozantinib, a multikinase inhibitor targeting vascular endothelial growth factor receptor, MET, and AXL, vs placebo in the second- and third-line setting in patients progressing on or intolerant to sorafenib. The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels. Overall, the adverse events reported in these trials were in line with the known safety profiles of the tested agents. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.
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Affiliation(s)
- Nicola Personeni
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
| | - Tiziana Pressiani
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milan, Italy
| | - Silvia Bozzarelli
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milan, Italy
| | - Lorenza Rimassa
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Rozzano 20089, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele 20090, Milan, Italy
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Giannini EG, Trevisani F. Ramucirumab as a second-line treatment for hepatocellular carcinoma: reaching out further to patients with elevated alpha-fetoprotein. Hepatobiliary Surg Nutr 2019; 8:515-518. [PMID: 31673543 DOI: 10.21037/hbsn.2019.04.19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, Ospedale Policlinico San Martino IRCCS per l'Oncologia, University of Genoa, Genoa, Italy
| | - Franco Trevisani
- Medical Semeiotics Unit, Sant'Orsola Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy
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Harding JJ, Zhu AX, Bauer TM, Choueiri TK, Drilon A, Voss MH, Fuchs CS, Abou-Alfa GK, Wijayawardana SR, Wang XA, Moser BA, Uruñuela A, Wacheck V, Bendell JC. A Phase Ib/II Study of Ramucirumab in Combination with Emibetuzumab in Patients with Advanced Cancer. Clin Cancer Res 2019; 25:5202-5211. [PMID: 31142504 DOI: 10.1158/1078-0432.ccr-18-4010] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 04/15/2019] [Accepted: 05/23/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE Inhibition of the VEGFR-2 blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect through activation of the hepatocyte growth factor receptor MET. Here we report results of the phase Ib/II study of ramucirumab, a monoclonal anti-VEGFR-2 antibody, plus the anti-MET mAb emibetuzumab. PATIENTS AND METHODS A 3+3 dose escalation of emibetuzumab plus ramucirumab (phase Ib) was followed by tumor-specific expansion cohorts. Primary objectives were to determine the recommended phase II dose and to evaluate antitumor activity. Secondary objectives included safety, pharmacokinetics, and immunogenicity. Tumoral MET expression was explored by immunohistochemistry (IHC). RESULTS A total of 97 patients with solid tumor [6 phase Ib, 16 gastric or gastroesophageal junction adenocarcinoma, 45 hepatocellular carcinoma (HCC), 15 renal cell carcinoma, and 15 non-small lung cancer] received emibetuzumab at 750 or 2,000 mg flat dosing plus ramucirumab at 8 mg/kg every 2 weeks. No dose-limiting toxicities were observed. Common adverse events were primarily mild or moderate and included fatigue (36.1%), peripheral edema (28.9%), and nausea (14.4%). Emibetuzumab exposures were similar as in previous studies with no apparent drug-drug interactions. Five partial responses (5.2%) were observed across all tumor types. The greatest antitumor activity was noted in HCC with a 6.7% overall response rate, 60% disease control rate, and 5.42 months (95% confidence interval, 1.64-8.12) progression-free survival (PFS). HCC with high MET expression showed improved PFS with approximately 3-fold increase in PFS (8.1 vs. 2.8 months) relative to low MET expression. CONCLUSIONS Ramucirumab plus emibetuzumab was safe and exhibited cytostatic antitumor activity. MET expression may help to select patients benefitting most from this combination treatment in select tumor types.
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Affiliation(s)
- James J Harding
- Memorial Sloan Kettering Cancer Center, New York, New York.
- Weill Cornell Medical College, New York, New York
| | - Andrew X Zhu
- Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - Todd M Bauer
- Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee
| | - Toni K Choueiri
- Yale Cancer Center, Smilow Cancer Hospital, New Haven, Connecticut
| | - Alexander Drilon
- Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | - Martin H Voss
- Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | - Charles S Fuchs
- Yale Cancer Center, Smilow Cancer Hospital, New Haven, Connecticut
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, New York
- Weill Cornell Medical College, New York, New York
| | | | | | | | | | | | - Johanna C Bendell
- Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee
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Mossenta M, Busato D, Baboci L, Cintio FD, Toffoli G, Bo MD. New Insight into Therapies Targeting Angiogenesis in Hepatocellular Carcinoma. Cancers (Basel) 2019; 11:E1086. [PMID: 31370258 PMCID: PMC6721310 DOI: 10.3390/cancers11081086] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 07/22/2019] [Accepted: 07/29/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy characterized by neoangiogenesis that is determined by an augmented production of proangiogenesis factors by tumor and adjacent cells. This unbalanced angiogenesis process is a key feature of HCC carcinogenesis and progression. Proangiogenic factors also have a relevant role in the generation and maintenance of an immunosuppressive tumor microenvironment. Several therapeutic options for HCC treatment are based on the inhibition of angiogenesis, both in the early/intermediate stages of the disease and in the late stages of the disease. Conventional treatment options employing antiangiogenic approaches provide for the starving of tumors of their blood supply to avoid the refueling of oxygen and nutrients. An emerging alternative point of view is the normalization of vasculature leading to enhance tumor perfusion and oxygenation, potentially capable, when proposed in combination with other treatments, to improve delivery and efficacy of other therapies, including immunotherapy with checkpoint inhibitors. The introduction of novel biomarkers can be useful for the definition of the most appropriate dose and scheduling for these combination treatment approaches. The present review provides a wide description of the pharmaceutical compounds with an antiangiogenic effect proposed for HCC treatment and investigated in clinical trials, including antibodies and small-molecule kinase inhibitors.
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Affiliation(s)
- Monica Mossenta
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Davide Busato
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Lorena Baboci
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy
| | - Federica Di Cintio
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy.
| | - Michele Dal Bo
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), 33081 Aviano (PN), Italy
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Raoul JL, Frenel JS, Raimbourg J, Gilabert M. Current options and future possibilities for the systemic treatment of hepatocellular carcinoma. Hepat Oncol 2019; 6:HEP11. [PMID: 31244990 PMCID: PMC6571544 DOI: 10.2217/hep-2019-0001] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 02/14/2019] [Indexed: 01/10/2023] Open
Abstract
Most hepatocellular carcinoma patients could not benefit from or experience disease recurrence after curative treatments. In 2007 sorafenib demonstrated efficacy in first line treatment of advanced hepatocellular carcinoma. After a decade of negative trials, in early 2019 we now have another tyrosine kinase inhibitor available in first line, lenvatinib, three other targeted therapies in second line post-sorafenib (regorafenib, cabozantinib and ramucirumab) and promising data from two immunotherapies (nivolumab and pembrolizumab). Unfortunately, no biomarkers have been identified to help guide our choice. In this short review we summarize the results of these different therapies and propose a therapeutic algorithm based on subgroup analysis. It is most likely that we will not have head-to-head comparisons in second line trials.
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Affiliation(s)
- Jean-Luc Raoul
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes 44805 Saint-Herblain, France
| | - Jean-Sébastien Frenel
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes 44805 Saint-Herblain, France
| | - Judith Raimbourg
- Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes 44805 Saint-Herblain, France
| | - Marine Gilabert
- Department of Medical Oncology, Institut Paoli-Calmettes, Cedex 9, Marseille 13000, France
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Natsume M, Shimura T, Iwasaki H, Okuda Y, Kitagawa M, Okamoto Y, Hayashi K, Kataoka H. Placental growth factor is a predictive biomarker for ramucirumab treatment in advanced gastric cancer. Cancer Chemother Pharmacol 2019; 83:1037-1046. [PMID: 30899983 DOI: 10.1007/s00280-019-03817-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 03/14/2019] [Indexed: 01/27/2023]
Abstract
PURPOSE Ramucirumab (RAM) has been used as the second-line standard chemotherapy for advanced gastric cancer (AGC) either alone or combination with paclitaxel (PTX). However, no predictive biomarkers have been identified for RAM treatment in AGC. METHODS We retrospectively identified 26 patients who received either RAM monotherapy or RAM + PTX therapy for AGC refractory to fluoropyrimidine and platinum agents from 2015 to 2018 at Nagoya City University Hospital. First, we extracted RNA using gastric cancer (GC) tissues from two responders and two non-responders, and then analyzed 24 VEGFR-related angiogenic genes. Subsequently, we examined the relationship between the expression of each angiogenic gene and RAM clinical activity in the entire cohort. Finally, we validated using in vitro angiogenesis assays using GC cells and microvascular endothelial cells. RESULTS We identified five angiogenic genes with aberrant expression between RAM responders and non-responders and placental growth factor (PlGF) was the most significant gene among them. Overall survival (P = 0.046) and progression-free survival (P = 0.016) were significantly shorter in the PlGF-high group than in the PlGF-low group. Overall response rates were 50% in the PlGF-low group and 0% in the PlGF-high group. In GC cells co-cultured with endothelial cells, PlGF gene silencing from GC cells significantly reinforced the inhibitory effect of RAM in the in vitro angiogenesis assay (tube formation assay and endothelial migration) through the inactivation of ERK, in comparison to the control GC cells. CONCLUSIONS PlGF gene expression in gastric cancer tissues could be a predictive indicator of AGC treatment by RAM.
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Affiliation(s)
- Makoto Natsume
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Takaya Shimura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.
| | - Hiroyasu Iwasaki
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Yusuke Okuda
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Mika Kitagawa
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Yasuyuki Okamoto
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Kazuki Hayashi
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
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Abstract
Ramucirumab is a fully humanized monoclonal antibody directed selectively at VEGFR-2 - a key player in the VEGF orchestra and angiogenic process. It has demonstrated clinical efficacy and a favorable safety profile in the treatment of a number of malignancies including gastric, lung, urothelial, colorectal and, most recently, advanced liver cancer. This article describes the recent Phase III trial results of ramucirumab in patients with hepatocellular carcinoma, including safety data and patient-reported outcomes, with particular emphasis on efficacy data in the patient population with baseline α-fetoprotein levels ≥400 ng/ml, traditionally considered a poor prognostic group.
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Affiliation(s)
- Fiona Turkes
- Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Ian Chau
- Department of Medicine, Royal Marsden Hospital NHS Foundation Trust, London, UK
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Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20:282-296. [PMID: 30665869 DOI: 10.1016/s1470-2045(18)30937-9] [Citation(s) in RCA: 1231] [Impact Index Per Article: 205.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 12/01/2018] [Accepted: 12/04/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher. METHODS REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433. FINDINGS Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0-12·5), median overall survival (8·5 months [95% CI 7·0-10·6] vs 7·3 months [5·4-9·1]; hazard ratio [HR] 0·710 [95% CI 0·531-0·949]; p=0·0199) and progression-free survival (2·8 months [2·8-4·1] vs 1·6 months [1·5-2·7]; 0·452 [0·339-0·603]; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group. The proportion of patients with an objective response did not differ significantly between groups (nine [5%] of 197 vs one [1%] of 95; p=0·1697). Median time to deterioration in FHSI-8 total scores (3·7 months [95% CI 2·8-4·4] vs 2·8 months [1·6-2·9]; HR 0·799 [95% CI 0·545-1·171]; p=0·238) and ECOG performance statuses (HR 1·082 [95% CI 0·639-1·832]; p=0·77) did not differ between groups. Grade 3 or worse treatment-emergent adverse events that occurred in at least 5% of patients in either group were hypertension (25 [13%] in the ramucirumab group vs five [5%] in the placebo group), hyponatraemia (11 [6%] vs 0) and increased aspartate aminotransferase (six [3%] vs five [5%]). Serious adverse events of any grade and cause occurred in 68 (35%) patients in the ramucirumab group and 28 (29%) patients in the placebo group. Three patients in the ramucirumab group died from treatment-emergent adverse events that were judged to be related to study treatment (one had acute kidney injury, one had hepatorenal syndrome, and one had renal failure). INTERPRETATION REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To our knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma. FUNDING Eli Lilly.
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Affiliation(s)
- Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Harvard Medical Center, Boston, MA, USA.
| | - Yoon-Koo Kang
- Asan Medical Center, University of Ulsan, Seoul, South Korea
| | - Chia-Jui Yen
- Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital Tainan, Taiwan; College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Richard S Finn
- Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | | | - Josep M Llovet
- Icahn School of Medicine at Mount Sinai, New York, NY, USA; Institut d'Investigations Biomèdiques, August Pi i Sunyer-Hospital Clinic Barcelona, Barcelona, Spain
| | | | | | | | - Ho Yeong Lim
- Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea
| | - Kun-Ming Rau
- Chang Gung Memorial Hospital-Kaohsiung Branch, Kaohsiung City, Taiwan; Hematology-Oncology Department, E-Da Cancer Hospital, Kaohsiung, Taiwan
| | | | - Izumi Ohno
- National Cancer Center Hospital East-Hepatobiliary and Pancreatic Oncology, Kashiwa, Chiba, Japan
| | | | - Bruno Daniele
- Azienda Ospedaliera G Rummo, Benevento, Benevento, Italy; Ospedale del Mare, Naples, Italy
| | - Dong Bok Shin
- Gachon University Gil Medical Center, Incheon, South Korea
| | - Guido Gerken
- Universtitätsklinikum Essen AöR, Essen, North Rhine-Westphalia, Germany
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Abou Faycal C, Gazzeri S, Eymin B. A VEGF-A/SOX2/SRSF2 network controls VEGFR1 pre-mRNA alternative splicing in lung carcinoma cells. Sci Rep 2019; 9:336. [PMID: 30674935 PMCID: PMC6344584 DOI: 10.1038/s41598-018-36728-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 11/22/2018] [Indexed: 12/19/2022] Open
Abstract
The splice variant sVEGFR1-i13 is a truncated version of the cell membrane-spanning VEGFR1 receptor that is devoid of its transmembrane and tyrosine kinase domains. We recently showed the contribution of sVEGFR1-i13 to the progression and the response of squamous lung carcinoma to anti-angiogenic therapies. In this study, we identify VEGF165, a splice variant of VEGF-A, as a regulator of sVEGFR1-i13 expression in these tumors, and further show that VEGF165 cooperates with the transcription factor SOX2 and the splicing factor SRSF2 to control sVEGFR1-i13 expression. We also demonstrate that anti-angiogenic therapies up-regulate sVEGFR1-i13 protein level in squamous lung carcinoma cells by a mechanism involving the VEGF165/SOX2/SRSF2 network. Collectively, our results identify for the first time a signaling network that controls VEGFR1 pre-mRNA alternative splicing in cancer cells.
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Affiliation(s)
- Cherine Abou Faycal
- INSERM U1209, CNRS UMR5309, Institute For Advanced Biosciences, Grenoble, 38042, France.,Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, 38041, France
| | - Sylvie Gazzeri
- INSERM U1209, CNRS UMR5309, Institute For Advanced Biosciences, Grenoble, 38042, France.,Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, 38041, France
| | - Beatrice Eymin
- INSERM U1209, CNRS UMR5309, Institute For Advanced Biosciences, Grenoble, 38042, France. .,Université Grenoble Alpes, Institut Albert Bonniot, Grenoble, 38041, France.
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50
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Jindal A, Thadi A, Shailubhai K. Hepatocellular Carcinoma: Etiology and Current and Future Drugs. J Clin Exp Hepatol 2019; 9:221-232. [PMID: 31024205 PMCID: PMC6477125 DOI: 10.1016/j.jceh.2019.01.004] [Citation(s) in RCA: 180] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 01/14/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is swiftly increasing in prevalence globally with a high mortality rate. The progression of HCC in patients is induced with advanced fibrosis, mainly cirrhosis, and hepatitis. The absence of proper preventive or curative treatment methods encouraged extensive research against HCC to develop new therapeutic strategies. The Food and Drug Administration-approved Nexavar (sorafenib) is used in the treatment of patients with unresectable HCC. In 2017, Stivarga (regorafenib) and Opdivo (nivolumab) got approved for patients with HCC after being treated with sorafenib, and in 2018, Lenvima (lenvatinib) got approved for patients with unresectable HCC. But, owing to the rapid drug resistance development and toxicities, these treatment options are not completely satisfactory. Therefore, there is an urgent need for new systemic combination therapies that target different signaling mechanisms, thereby decreasing the prospect of cancer cells developing resistance to treatment. In this review, HCC etiology and new therapeutic strategies that include currently approved drugs and other potential candidates of HCC such as Milciclib, palbociclib, galunisertib, ipafricept, and ramucirumab are evaluated.
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Key Words
- AMP, adenosine monophosphate
- AMPK, AMP-activated protein kinase
- ATP, adenosine 5′-triphosphate
- BMF, Bcl2 modifying factor
- BMI, body mass index
- CDK, cyclin-dependent kinase
- CTGF, connective tissue growth factor
- CTL, cytotoxic T lymphocyte
- CTLA, cytotoxic T-lymphocyte-associated protein
- ECM, extracellular matrix
- EFGR, endothelial growth factor receptor
- EGFR, epidermal growth factor receptor
- EMT, Epithelial–mesenchymal transition
- ERK, extracellular signal-regulated kinase
- FDA, Food and Drug Administration
- GFG, fibroblast growth factor
- HBV, hepatitis B virus
- HBcAg, hepatitis B core antibody
- HBsAg, HBV surface antigen
- HCC, Hepatocellular carcinoma
- HCV, hepatitis B virus
- HDV, hepatitis D virus
- HIF, hypoxia-inducible factor
- HIV, human immunodeficiency virus
- IGFR, insulin-like growth factor
- JAK, janus kinase
- MAPK, mitogen-activated protein kinase
- MDSC, myeloid-derived suppressor cell
- NASH, nonalcoholic steatohepatitis
- NK, natural killer
- NKT, natural killer T cell
- ORR, objective response rate
- OS, overall survival
- PAPSS1, 3′-phosphoadenosine 5′-phosphosulfate synthase 1
- PD-L1, programmed death ligand1
- PD1, programmed cell death protein 1
- PDGFR, platelet-derived growth factor receptor
- PEDF, pigment epithelium-derived factor
- PFS, progression-free survival
- PI3K, phosphoinositide 3-kinases
- PTEN, phosphatase and tensin homolog
- PUMA, p53 upregulated modulator of apoptosis
- RFA, radiofrequency ablation
- Rb, retinoblastoma protein
- SCF, stem cell factor
- SHP1, src homology 2 domain–containing phosphatase 1
- STAT3, signal transducer and activator of transcription 3
- TACE, transarterial chemoembolization
- TGF 1, transforming growth factor-1
- TK, tyrosine kinase
- TKI, Tyrosine kinase inhibitor
- TRKA, tropomyosin receptor kinase A
- Treg, regulatory T cells
- VEGF, vascular endothelial growth factor
- VEGFR, vascular endothelial growth factor receptor
- bFGF, basic fibroblast growth factor
- combination therapy
- cyclin-dependent kinase inhibitors
- hepatocellular carcinoma
- hepatology
- tyrosine kinase inhibitors
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Affiliation(s)
- Aastha Jindal
- Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
- Address for correspondence: Aastha Jindal, Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA.
| | - Anusha Thadi
- Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
| | - Kunwar Shailubhai
- Research and Development Center, Baruch S. Blumberg Institute, Doylestown, PA 18902, USA
- Research & Development, Tiziana Lifesciences, Doylestown, PA 18902, USA
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