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      Application and Resistance Mechanisms of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma

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          Abstract

          Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), is one of the preferred targeted drugs for the treatment of advanced hepatocellular carcinoma (aHCC). Since the REFLECT study showed that lenvatinib was noninferior to sorafenib in overall survival (OS), lenvatinib monotherapy has been widely used for aHCC. Moreover, lenvatinib combination therapy, especially lenvatinib combined with immune checkpoint inhibitors (ICIs), has shown more encouraging clinical results. However, drug development and comprehensive treatment have not significantly improved the prognosis, and lenvatinib resistance is often encountered in treatment. The underlying molecular mechanism of lenvatinib resistance is still unclear, and studies to solve drug resistance are ongoing. The molecular mechanisms of lenvatinib resistance in patients with aHCC include the regulation of signaling pathways, the regulation of noncoding RNAs, the impact of the immune microenvironment, tumor stem cell activation and other mechanisms. This review aims to (1) summarize the progress of lenvatinib in treating aHCC, (2) delineate the known lenvatinib resistance mechanisms of current therapy, and (3) describe the development of therapeutic methods intended to overcome these resistance mechanisms.

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          Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

          Richard S Finn, Shukui Qin, Masafumi Ikeda … (2020)
          The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.
          Article 0 comments Cited 2906 times – based on 0 reviews     Review now
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            Hepatocellular carcinoma

            Josep Llovet, Robin Kate Kelley, Augusto Villanueva … (2021)
            Liver cancer remains a global health challenge, with an estimated incidence of >1 million cases by 2025. Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ~90% of cases. Infection by hepatitis B virus and hepatitis C virus are the main risk factors for HCC development, although non-alcoholic steatohepatitis associated with metabolic syndrome or diabetes mellitus is becoming a more frequent risk factor in the West. Moreover, non-alcoholic steatohepatitis-associated HCC has a unique molecular pathogenesis. Approximately 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. Diagnosis based upon non-invasive criteria is currently challenged by the need for molecular information that requires tissue or liquid biopsies. The current major advancements have impacted the management of patients with advanced HCC. Six systemic therapies have been approved based on phase III trials (atezolizumab plus bevacizumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and three additional therapies have obtained accelerated FDA approval owing to evidence of efficacy. New trials are exploring combination therapies, including checkpoint inhibitors and tyrosine kinase inhibitors or anti-VEGF therapies, or even combinations of two immunotherapy regimens. The outcomes of these trials are expected to change the landscape of HCC management at all evolutionary stages.
            Article 0 comments Cited 2350 times – based on 0 reviews     Review now
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              Sorafenib in advanced hepatocellular carcinoma.

              Josep Llovet, Sergio Ricci, Vincenzo Mazzaferro … (2008)
              No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma. In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group. In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.) 2008 Massachusetts Medical Society
              Article 0 comments Cited 2338 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Hepatocell Carcinoma
                Journal ID (iso-abbrev): J Hepatocell Carcinoma
                Journal ID (publisher-id): jhc
                Title: Journal of Hepatocellular Carcinoma
                Publisher: Dove
                ISSN (Electronic): 2253-5969
                Publication date (Electronic): 10 July 2023
                Publication date Collection: 2023
                Volume: 10
                Pages: 1069-1083
                Affiliations
                [1 ]Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou, 510120, People’s Republic of China
                [2 ]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou, 510120, People’s Republic of China
                [3 ]Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital , Zhengzhou, 450008, People’s Republic of China
                Author notes
                Correspondence: Yongcong Yan; Zhiyu Xiao, Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Yanjiang West Road #107, Guangzhou, 510120, People’s Republic of China, Tel +86-15800039176; +86-13682283695, Fax +86 20 34071073, Email yanyc3@mail.sysu.edu.cn; xiaozhiy@mail.sysu.edu.cn
                Author information
                http://orcid.org/0000-0002-4039-4353
                http://orcid.org/0000-0002-3323-5397
                http://orcid.org/0000-0001-9254-2330
                Article
                Publisher ID: 411806
                DOI: 10.2147/JHC.S411806
                PMC ID: 10348321
                PubMed ID: 37457652
                SO-VID: 9571c6bd-7034-4d71-9c2e-cc0605f611b3
                Copyright © © 2023 Tao et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 09 March 2023
                Date accepted : 01 June 2023
                Page count
                Figures: 2, Tables: 4, References: 99, Pages: 15
                Funding
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: Project funded by China Postdoctoral Science Foundation;
                Funded by: Guangdong Basic and Applied Basic Research Foundation;
                Funded by: Science and Technology Program of Guangzhou;
                This work was supported by the National Natural Science Foundation of China (No. 82103090); Project funded by China Postdoctoral Science Foundation (2021M703742); Guangdong Basic and Applied Basic Research Foundation (No. 2022A1515012391); Science and Technology Program of Guangzhou (No.202201020311).
                Categories
                Subject: Review

                Keywords: lenvatinib,application,drug resistance,hepatocellular carcinoma
                Data availability:
                Keywords: lenvatinib, application, drug resistance, hepatocellular carcinoma

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