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ABSTRACT
Introduction
: The evolving therapeutic landscape of advanced hepatocellular carcinoma (HCC) includes the increasing implementation of target-therapy and immunotherapy. Lenvatinib, a multi-target tyrosine kinase inhibitor (TKI), is an emerging first-line therapy for hepatocellular carcinoma. Its approval has changed the scenario of first-line therapies for advanced HCC, where just sorafenib proved clinical efficacy for over a decade.
Areas covered
: The current evidence on the role of lenvatinib for patients with advanced HCC is reviewed in this article. Particularly, therapeutic mechanisms and clinical efficacy of lenvatinib are summarized and the management of adverse events is discussed. In addition, future perspectives on the emerging role of combine therapy for HCC are highlighted.
Expert Opinion
In the first line, lenvatinib was found to be non-inferior to sorafenib for overall survival, with significantly better progression-free survival and objective response rate. Immune checkpoint inhibitors (ICIs) are now part of HCC treatment, and recently the combination of atezolizumab plus bevacizumab has become the recommended standard of care first-line therapy for selected patients. The antitumor and immunomodulatory activities that lenvatinib shows in preclinical studies, and the positive outcomes achieved using a combination of lenvatinib plus ICIs, open new perspectives for advanced HCC treatment.
Article highlights
Hepatocellular carcinoma (HCC) accounts for about 80% of liver tumors and it is characterized by a poor-prognosis and high recurrence rates.
Sorafenib, an oral inhibitor of vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptor (PDGFR), and RAF kinases, was the only first-line treatment with proven efficacy in advanced HCC for over a decade.
Lenvatinib is an emerging first-line therapy for HCC that inhibits multiple tyrosine kinases receptors (VEGFR 1-3, FGFR 1-4, PDGFR-a, RET, and c-KIT) considered drivers in the development of many types of cancer.
The REFLECT trial has recently demonstrated that lenvatinib is non-inferior to sorafenib in terms of overall survival with an improvement in progression-free survival, time to progression, and objective response rate.
Considering the balance between efficacy and safety of lenvatinib, and to minimize early dose reduction or therapy interruption, the recommended starting dose has been established in relation to body weight (12 mg for patients weighing more than 60 kg and 8 mg for those <60 kg)
The combination of atezolizumab plus bevacizumab was recently shown to be superior to sorafenib in terms of overall and progression-free survival becoming the recommended standard of care first-line therapy for selected patients.
Lenvatinib regulates tumor immune microenvironment reducing negative-regulatory immune cells and increasing activated CD8+ T cells, demonstrating that the combination of immune checkpoint inhibitors and targeted agents may have synergistic effects.
Based on promising data from Phase Ib study, a phase III trial, LEAP-002, is evaluating the efficacy and safety of lenvatinib in combination with pembrolizumab as first-line therapy in patients with advanced HCC and well-preserved liver function.
Additional studies are required to explore the biomarkers that could predict efficacy response and resistance to lenvatinib, that remains the principal cause of treatment failure during targeted therapies, to better define patients to be treated and avoid unnecessary risk.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.