Systemic Therapy for Advanced Hepatocellular Carcinoma: An Update of a Rapidly Evolving Field

Hepatocellular carcinoma (HCC) incidence and mortality have shown an unfavorable upward trend over the last two decades, especially in developed countries. More than one-sixth of the patients have advanced HCC at presentation. Systemic therapy remains the treatment of choice for these patients. Current options include tyrosine kinase inhibitors (TKIs) and immunotherapy. This review aims to summarize current knowledge on the rapidly evolving field of systemic therapy with several newly approved medications over the last year. Sorafenib remains one of the first-line treatment choices for patients with hepatitis C etiology, intermediate to advanced HCC stage, and Child-Pugh class A. Lenvatinib is the other first-line drug that might have better efficacy in non–hepatitis C etiologies and advanced HCC without portal vein thrombosis. Patients intolerant to first-line therapy might benefit from immunotherapy with nivolumab or pembrolizumab. In those who fail first-line therapy, the choice should be based on the side effects related to previous treatment, performance status, and underlying liver dysfunction. Ongoing studies are investigating immunotherapy alone or immunotherapy in combination with TKIs as first-line therapy. Several second-line options for combination systemic therapy and systemic plus local-regional treatment are under investigation. Future studies should focus on identifying reliable biomarkers to predict response to therapy and to better stratify patients at high risk for progression. Multidisciplinary approach is pivotal for successful outcomes in patients with advanced HCC. Hepatocellular carcinoma (HCC) incidence and mortality have shown an unfavorable upward trend over the last two decades, especially in developed countries. More than one-sixth of the patients have advanced HCC at presentation. Systemic therapy remains the treatment of choice for these patients. Current options include tyrosine kinase inhibitors (TKIs) and immunotherapy. This review aims to summarize current knowledge on the rapidly evolving field of systemic therapy with several newly approved medications over the last year. Sorafenib remains one of the first-line treatment choices for patients with hepatitis C etiology, intermediate to advanced HCC stage, and Child-Pugh class A. Lenvatinib is the other first-line drug that might have better efficacy in non–hepatitis C etiologies and advanced HCC without portal vein thrombosis. Patients intolerant to first-line therapy might benefit from immunotherapy with nivolumab or pembrolizumab. In those who fail first-line therapy, the choice should be based on the side effects related to previous treatment, performance status, and underlying liver dysfunction. Ongoing studies are investigating immunotherapy alone or immunotherapy in combination with TKIs as first-line therapy. Several second-line options for combination systemic therapy and systemic plus local-regional treatment are under investigation. Future studies should focus on identifying reliable biomarkers to predict response to therapy and to better stratify patients at high risk for progression. Multidisciplinary approach is pivotal for successful outcomes in patients with advanced HCC. Over the last 25 years, hepatocellular carcinoma (HCC) incidence has shown continuous rise worldwide and is more pronounced in developed countries.1Liu Z. Jiang Y. Yuan H. et al.The trends in incidence of primary liver cancer caused by specific etiologies: results from the Global Burden of Disease Study 2016 and implications for liver cancer prevention.J Hepatol. 2019; 70: 674-683Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar HCC remains a leading causes of cancer-related mortality in the USA.2Bertuccio P. Turati F. Carioli G. et al.Global trends and predictions in hepatocellular carcinoma mortality.J Hepatol. 2017; 67: 302-309Abstract Full Text Full Text PDF PubMed Scopus (410) Google Scholar The estimated 1- and 2-year survival of untreated HCC is 17.5% and 7.3%, respectively.3Cabibbo G. Enea M. Attanasio M. et al.A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma.Hepatology. 2010; 51: 1274-1283Crossref PubMed Scopus (325) Google Scholar Although there has been an increase in early-diagnosed HCC, 16% have distant metastases at the time of presentation and 85% have lymphovascular invasion on final pathology.4Njei B. Rotman Y. Ditah I. et al.Emerging trends in hepatocellular carcinoma incidence and mortality.Hepatology. 2015; 61: 191-199Crossref PubMed Scopus (379) Google Scholar Systemic chemotherapy remains the treatment of choice for patients with advanced HCC who are not suitable for resection, liver transplantation (LT), or local-regional therapy (LRT). The aim of this review is to update and summarize knowledge on currently approved systemic therapies for advanced HCC in the light of several recent medication approvals and to provide guidance on treatment selection. Current systemic therapy of HCC consists of receptor tyrosine kinase inhibitors (TKIs) and checkpoint inhibitors. Kinases are a class of enzymes that catalyze the transfer of phosphate groups from adenosine triphosphate (ATP) onto amino acid residues (tyrosine, serine, and threonine) of key proteins, which results in signal transduction associated with cell differentiation, proliferation, or death.5Wang Z. Cole P.A. Catalytic mechanisms and regulation of protein kinases.Methods Enzymol. 2014; 548: 1-21Crossref PubMed Scopus (95) Google Scholar Overexpression of their receptors, in particular of receptor tyrosine kinases (RTKs) in various cancers, has led to the development of more than 20 TKI drugs. RTKs act as receptors for growth factors, cytokines, hormones, and other extracellular signaling molecules that activate them after binding to their extracellular domain.6Regad T. Targeting RTK signaling pathways in cancer.Cancers. 2015; 7: 1758-1784Crossref PubMed Scopus (235) Google Scholar Some of the most important RTK subfamilies are vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), mast/stem cell growth factor receptor (c-KIT), and hepatocyte growth factor receptor (c-MET). Alterations of RTKs could result in deregulation of signaling pathways, thus triggering cell proliferation and tumor formation.7Jiao Q. Bi L. Ren Y. et al.Advances in studies of tyrosine kinase inhibitors and their acquired resistance.Mol Cancer. 2018; 17: 36Crossref PubMed Scopus (190) Google Scholar TKIs compete with ATP for ATP-binding sites and decrease tyrosine kinase phosphorylation that leads to inhibition of tumor growth, angiogenesis, and stimulation of tumor cell apoptosis. Over the last decade, immune checkpoint inhibitors have emerged as a promising treatment in cancer therapy. Their effect is based on targeting immune checkpoint receptors that are negative regulators of antitumor immunity and are upregulated in tumor tissues.8Ribas A. Wolchok J.D. Cancer immunotherapy using checkpoint blockade.Science. 2018; 359: 1350-1355Crossref PubMed Scopus (2961) Google Scholar The result is activation of preexisting cytotoxic T lymphocytes. These agents may result in long-lasting tumor regression even in diffusely metastatic cancers. The antibodies identified to date that trigger antitumor immune response target the cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) or programmed cell death-1 (PD-1) pathways. CTLA-4 affects T-cell activity and proliferation, mainly in the priming phase of the immune response in lymph nodes, whereas PD-1 acts during the effector phase, predominantly in peripheral tissues.9Buchbinder E.I. Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition.Am J Clin Oncol. 2016; 39: 98-106Crossref PubMed Scopus (1240) Google Scholar A major concern with this therapy remains immune-related adverse events (irAEs) that could affect the colon, liver, lungs, thyroid gland, pituitary, heart, nervous system, and skin.10Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade.N Engl J Med. 2018; 378: 158-168Crossref PubMed Scopus (2135) Google Scholar Although irAEs can be usually managed with discontinuation of chemotherapy and corticosteroids therapy, a recent meta-analysis reported that fatal toxic events can occur in 0.3%–1.3% of treated patients, mainly in the early phases of treatment.11Wang D.Y. Salem J.E. Cohen J.V. et al.Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis.JAMA Oncol. 2018; 4: 1721-1728Crossref PubMed Scopus (1083) Google Scholar The most common targets and mechanism of action of currently approved medications for treatment of advanced HCC are showed in Figure 1. Sorafenib (Nexavar®; Bayer, Germany) was discovered in the late 1990s and approved for first-line treatment of advanced HCC in the USA in 2007 and later worldwide. It has remained the standard of care and the only available option for treatment of advanced HCC for more than 10 years. Sorafenib is an oral multitargeted TKI with antiangiogenic, apoptotic, and antiproliferative activity.12Liu L. Cao Y. Chen C. et al.Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5.Cancer Res. 2006; 66: 11851-11858Crossref PubMed Scopus (1240) Google Scholar It inhibits serine-threonine kinases: wild-type and mutant B-Raf as well as Raf1 (or C-Raf) and directly blocks autophosphorylation of RTKs for VEGFRs 1, 2, and 3 and PDGFR-β, fms-like tyrosine kinase 3 (FLT-3), c-KIT, and rearranged during transfection (RET).13Wilhelm S.M. Carter C. Tang L. et al.BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis.Cancer Res. 2004; 64: 7099-7109Crossref PubMed Scopus (3525) Google Scholar Sorafenib approval was based on a multicenter, phase 3, randomized controlled trial (RCT) Sorafenib HCC Assessment Randomized Protocol (SHARP)14Llovet J.M. Ricci S. Mazzaferro V. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (8967) Google Scholar that showed benefit on median overall survival (OS) and delay in radiologic progression (Table 1). A phase 3 study based on Asian population confirmed its beneficial effect in this cohort as well.15Cheng A.L. Kang Y.K. Chen Z. et al.Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.Lancet Oncol. 2009; 10: 25-34Abstract Full Text Full Text PDF PubMed Scopus (4421) Google ScholarTable 1Main Trials Results of Currently Approved Medications for Advanced HCC.Clinical trialOverall survival (months)Objective responseaThe percentage of patients with complete or partial response.Drug-related adverse events (grade 3/4)Permanent discontinuation due to adverse eventsDose reduction due to adverse effectsSorafenib vs. placeboSHARP14Llovet J.M. Ricci S. Mazzaferro V. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (8967) Google ScholarPhase 310.7 vs. 7.9;HR, 0.69 (CI, 0.55–0.87) P < 0.0012% vs 1%Diarrhea, HFSR, hypertension, abdominal pain11% vs 5%26% vs 7%Sorafenib vs. placeboAsian-Pacific15Cheng A.L. Kang Y.K. Chen Z. et al.Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.Lancet Oncol. 2009; 10: 25-34Abstract Full Text Full Text PDF PubMed Scopus (4421) Google ScholarPhase 36.5 vs. 4.2;HR, 0.68 (CI, 0.50–0.93)P = 0.0143.3% vs 1.3%HFSR, diarrhea, fatigue, hypertension20% vs 13%31% vs 3%Lenvatinib vs. sorafenibREFLECT28Kudo M. Finn R.S. Qin S. et al.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.Lancet. 2018; 391: 1163-1173Abstract Full Text Full Text PDF PubMed Scopus (2446) Google ScholarPhase 313.6 vs. 12.3;HR, 0.92 (CI, 0.79–1.06)24% vs 9%57% lenvatinib vs 49% sorafenib9% vs 7%37% vs 38%Regorafenib vs. placeboRESORCE30Bruix J. Qin S. Merle P. et al.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017; 389: 56-66Abstract Full Text Full Text PDF PubMed Scopus (2159) Google ScholarPhase 310.6 vs. 7.8;HR, 0.63 (CI, 0.50–0.79) P < 0.000111% vs 4%Hypertension, HFSR, fatigue, diarrhea10% vs 4%54% vs 10%Cabozantinib vs. placeboCELESTIAL37Abou-Alfa G.K. Meyer T. Cheng A.L. et al.Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.N Engl J Med. 2018; 379: 54-63Crossref PubMed Scopus (1176) Google ScholarPhase 310.2 vs. 8.0;HR, 0.76 (CI, 0.63–0.92)P = 0.0054% vs <1%HFSR, hypertension, AST increase, diarrhea16% vs 3%62% vs 13%NivolumabCheckMate 04041El-Khoueiry A.B. Sangro B. Yau T. et al.Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.Lancet. 2017; 389: 2492-2502Abstract Full Text Full Text PDF PubMed Scopus (2467) Google ScholarPhase 1/2–15% in dose escalation20% in dose-expansion phaseAST and ALT increase, lipase and amylase increase, pruritus11%–PembrolizumabKEYNOTE-22442Zhu A.X. Finn R.S. Edeline J. et al.Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.Lancet Oncol. 2018; 19: 940-952Abstract Full Text Full Text PDF PubMed Scopus (1333) Google ScholarPhase 2–17%Fatigue, AST and ALT increase, hyperbilirubinemia, adrenal insufficiency5%–ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, 95% confidence interval; HCC, hepatocellular carcinoma; HFSR, hand-foot skin reaction; HR, hazard ratio.a The percentage of patients with complete or partial response. Open table in a new tab ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, 95% confidence interval; HCC, hepatocellular carcinoma; HFSR, hand-foot skin reaction; HR, hazard ratio. Two real-life observational studies assessed the use of sorafenib in different populations of patients with HCC.16Marrero J.A. Kudo M. Venook A.P. et al.Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study.J Hepatol. 2016; 65: 1140-1147Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 17Iavarone M. Cabibbo G. Piscaglia F. et al.Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy.Hepatology. 2011; 54: 2055-2063Crossref PubMed Scopus (290) Google Scholar Global Investigation of therapeutic Decisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON)16Marrero J.A. Kudo M. Venook A.P. et al.Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study.J Hepatol. 2016; 65: 1140-1147Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar demonstrated better OS of Child-Turcotte-Pugh (CTP) class A patients (13.6 months) than that of CTP class B (5.2 months) and CTP class C (2.6 months) patients. The safety profile was similar between groups. SOraFenib Italian Assessment (SOFIA)17Iavarone M. Cabibbo G. Piscaglia F. et al.Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy.Hepatology. 2011; 54: 2055-2063Crossref PubMed Scopus (290) Google Scholar showed greater benefit in patients with less advanced tumors based on Barcelona Clinic Liver Cancer (BCLC) staging system: Those with BCLC-B responded better than BCLC-C group. Overall, 40% of patients in this study discontinued sorafenib because of side effects. Advanced Eastern Cooperative Oncology Group (ECOG) performance status, macrovascular invasion, extrahepatic spread, early radiologic progression at 2 months, and sorafenib dose were independent predictors of mortality. An analysis based on pooled data from the SHARP and Asian-Pacific trials noted that patients with HCC without extrahepatic spread, with hepatitis C virus (HCV) etiology, and low neutrophil-to-lymphocyte ratio had the greatest benefit of sorafenib therapy.18Bruix J. Cheng A.L. Meinhardt G. et al.Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies.J Hepatol. 2017; 67: 999-1008Abstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar Another prognostic factor was development of hand-foot skin reaction of grade 2 or more within 60 days of sorafenib initiation which was associated with significant decrease in mortality.19Wang E. Xia D. Bai W. et al.Hand-foot-skin reaction of grade >/= 2 within sixty days as the optimal clinical marker best help predict survival in sorafenib therapy for HCC.Investig New Drugs. 2019 Jun; 37: 401-414Google Scholar Meta-analysis based on more than 2000 patients confirmed that dermatological adverse events due to sorafenib were associated with longer survival.20Diaz-Gonzalez A. Sanduzzi-Zamparelli M. Sapena V. et al.Systematic review with meta-analysis: the critical role of dermatological events in patients with hepatocellular carcinoma treated with sorafenib.Aliment Pharmacol Ther. 2019; 49: 482-491Crossref PubMed Scopus (31) Google Scholar The rationale for combining LRT with sorafenib is based on previous evidence that transarterial chemoembolization (TACE) could cause hypoxia, enhanced microvessel density, and increased VEGF expression in HCC cells.21Xiao E.H. Guo D. Bian D.J. Effect of preoperative transcatheter arterial chemoembolization on angiogenesis of hepatocellular carcinoma cells.World J Gastroenterol. 2009; 15: 4582-4586Crossref PubMed Scopus (36) Google Scholar However, clinical trials to date have shown conflicting results. A recent meta-analysis based on 27 studies published over the last eight years demonstrated that the combination of sorafenib with TACE vs. TACE alone was superior in terms of time to progression (TTP), but not for OS.22Li L. Zhao W. Wang M. et al.Transarterial chemoembolization plus sorafenib for the management of unresectable hepatocellular carcinoma: a systematic review and meta-analysis.BMC Gastroenterol. 2018; 18: 138Google Scholar An open-label phase 2 trial that investigated the benefit of TACE plus sorafenib (started 2–3 weeks before the procedure) vs. TACE alone (TACTICS trial)23Kudo M. Ueshima K. Torimura T. et al.Randomized, open label, multicenter, phase II trial of transcatheter arterial chemoembolization (TACE) therapy in combination with sorafenib as compared to TACE alone in patients with hepatocellular carcinoma: TACTICS trial.J Clin Oncol. 2018; 36 (Abstract)Google Scholar in patients with good performance status, CTP score ≤7, and intermediate-stage HCC (BCLC-B) showed promising results with improved progression-free survival (PFS) in combination group vs. TACE alone (25.2 vs 13.5 months) and TTP (26.7 vs 16.4 months; HR 0.54), but the results of OS are pending. A different design was used in a phase 3 trial that compared sorafenib vs. TACE plus sorafenib in patients with advanced HCC who failed LRT (sorafenib with or without cTACE in patients with advanced HCC (STAH) trial).24Park J.W. Kim Y.J. Kim D.Y. et al.Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: the phase III STAH trial.J Hepatol. 2019; 70: 684-691Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar There was no improvement in OS, although all secondary outcomes such as PFS, TTP, and tumor response rate were significantly longer in the sorafenib + TACE group. The effect of selective internal radiation therapy vs. sorafenib was assessed in a phase 2 RCT SORAfenib in combination with local MICrotherapy guided by gadolinium-EOB-DTPA-enhanced magnetic resonance imaging (SORAMIC), which did not show benefit in OS between the two groups, but in a subgroup analysis, yttrium-90 + sorafenib improved OS in patients younger than 65 years, in those with nonalcoholic fatty liver disease etiology, and in those without cirrhosis.25Ricke J. Sangro B. Amthauer H. et al.The impact of combining Selective Internal Radiation Therapy (SIRT) with Sorafenib on overall survival in patients with advanced hepatocellular carcinoma: the Soramic trial palliative cohort. [Abstract].J Hepatol. 2018; 68: S102Abstract Full Text PDF Google Scholar Overall, sorafenib has shown to be more efficacious in patients with HCV, intermediate to advanced HCC stage, and CTP class A. Patients who experience hand-foot reaction seem to respond better to therapy, but this remains to be proven. Although no significant difference in safety was found in most studies, patients with more advanced liver disease showed a greater number of adverse events, requiring dose reduction or drug discontinuation. Lenvatinib (Lenvima®; Eisai Inc., Japan) is a multitargeted TKI that inhibits VEGFR1-3, PDGFR-α, RET, and KIT. The distinctive feature of this molecule is the additional inhibition of FGFRs 1–4 of HCC tumor cells.26Yamamoto Y. Matsui J. Matsushima T. et al.Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage.Vasc Cell. 2014; 6: 18Crossref PubMed Scopus (281) Google Scholar A recent study that used an animal model of HCC noted that lenvatinib had immunomodulatory activity that enhanced its antitumor effect, especially when combined with anti–PD-1 antibody.27Kimura T. Kato Y. Ozawa Y. et al.Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model.Cancer Sci. 2018; 109: 3993-4002Crossref PubMed Scopus (148) Google Scholar In 2018, lenvatinib was approved for first-line therapy of HCC initially in Japan and later in the USA, Europe, and China. The approval was based on the results of a randomized, open-label, phase 3 noninferiority trial comparing lenvatinib 12 mg for body weight ≥60 kg and 8 mg for body weight <60 kg and sorafenib 400 mg twice daily (REFLECT trial).28Kudo M. Finn R.S. Qin S. et al.Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.Lancet. 2018; 391: 1163-1173Abstract Full Text Full Text PDF PubMed Scopus (2446) Google Scholar Patients with unresectable HCC, BCLC-B and C, CTP class A, and no prior systemic treatment were included. The study did not enroll patients with >50% liver involvement and/or main portal vein or biliary invasion. Lenvatinib showed noninferiority regarding mean OS but did not reach superiority. There was statistically significant improvement with lenvatinib in all secondary efficacy endpoints: longer median PFS and TTP as well as greater objective response. Lenvatinib demonstrated greater benefit in OS in those with alpha-fetoprotein (AFP) ≥ 200 ng/ml, although patients were not stratified by AFP level at enrollment. Subgroup analyses showed it was less effective in patients from Western countries, without extrahepatic spread, and with HCV etiology. The most common treatment-emergent adverse effect (TEAE) was hypertension. After correction for treatment duration, TEAEs were comparable between arms. However, there was delayed deterioration in the quality of life of patients taking lenvatinib. More than one-third of the patients in this trial received poststudy treatment after failure of the studied medications. Among those, median OS was 21 and 17 months and objective response rate was 27.6% and 8.7% in lenvatinib vs. sorafenib arms, respectively. Currently, a large phase 3 trial is assessing the efficacy of a combination of lenvatinib with pembrolizumab as first-line therapy (NCT03713593) and a phase 1 trial is assessing the efficacy of a combination of lenvatinib with nivolumab (NCT03418922). Regorafenib (Stivarga® Bayer, Germany) is a multitargeted TKI with very similar structure as sorafenib, but it is considered a second-generation drug because of its improved target affinity and higher potency. It blocks the activity of angiogenic (VEGFR1, VEGFR2, VEGFR3, and tyrosine kinase with immunoglobulin and epidermal growth factor (TIE-2)), stromal (PDGFR-β and FGFR), and oncogenic (Raf, RET, and c-KIT) RTKs.29Wilhelm S.M. Dumas J. Adnane L. et al.Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity.Int J Cancer. 2011; 129: 245-255Crossref PubMed Scopus (944) Google Scholar Regorafenib was approved in the USA and Europe in 2017 for patients who failed sorafenib therapy. The approval was based on the positive results of a phase 3 RCT that compared regorafenib 160 mg daily with placebo administered 3 weeks per month with one week off in patients who progressed on sorafenib (Regorafenib after sorafenib in patients with hepatocellular carcinoma (RESORCE) trial).30Bruix J. Qin S. Merle P. et al.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017; 389: 56-66Abstract Full Text Full Text PDF PubMed Scopus (2159) Google Scholar The studied population consisted of patients with a good performance status (ECOG 0 and 1); most had advanced HCC (BCLC-C) and preserved liver function (CTP class A). In comparison with prior trials, patients were stratified by AFP level, vascular invasion, and extrahepatic spread. This was prompted by an analysis that demonstrated the endpoint for discontinuing first-line therapy should be radiological and not symptomatic progression and that there was an association between patterns of progression and postprogression survival, with new extrahepatic nodule being the strongest predictor of radiologic tumor progression.31Reig M. Rimola J. Torres F. et al.Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design.Hepatology. 2013; 58: 2023-2031Crossref PubMed Scopus (184) Google Scholar Only patients who tolerated sorafenib were included in the trial, and the reason for discontinuation had to be radiological progression.30Bruix J. Qin S. Merle P. et al.Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet. 2017; 389: 56-66Abstract Full Text Full Text PDF PubMed Scopus (2159) Google Scholar Regorafenib met the primary endpoint with a median OS of 10.6 months in the regorafenib arm vs. 7.8 months in the placebo arm. The OS favored regorafenib in all subgroups, especially in patients <65 years and/or with extrahepatic spread, CTP class A score 5, and hepatitis B virus (HBV) etiology. The TEAEs of regorafenib were similar to those of sorafenib. A secondary analysis of the RESORCE trial demonstrated that regorafenib provided benefit on OS irrespective of the last sorafenib dose or TTP on sorafenib with no significant differences in safety.32Finn R.S. Merle P. Granito A. et al.Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase III RESORCE trial.J Hepatol. 2018; 69: 353-358Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar The median OS was 26 months in the sorafenib-regorafenib group compared with 19 months in the sorafenib-placebo group. This beneficial effect suggests patients with progressive HCC, despite LRT, should be started on systemic therapy early, while liver function is preserved, and should be considered for second-line therapy, despite disease progression. On the other hand, cost-effective analyses showed only modest incremental benefit at a relatively high incremental cost, suggesting regorafenib treatment is not cost-effective and patients should be carefully selected before being considered for therapy.33Shlomai A. Leshno M. Goldstein D.A. Regorafenib treatment for patients with hepatocellular carcinoma who progressed on sorafenib-A cost-effectiveness analysis.PLoS One. 2018; 13 (e0207132)Google Scholar A recent analysis of plasma and tissue samples of participants of RESORCE trial suggested five proteins known to play a role in inflammation and in HCC pathogenesis, and nine microRNAs could be potentially used as prognostic markers for increased OS after regorafenib therapy.34Teufel M. Seidel H. Kochert K. et al.Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma.Gastroenterology. 2019 May; 156: 1731-1741Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar Interestingly, neither AFP nor c-MET was predictive of treatment benefit. Cabozantinib (Cabometyx®; Exelixis Inc., USA) is a TKI that inhibits VEGFR2, c-MET, and AXL receptor tyrosine kinase (RTK implicated in metastases development).35Yakes F.M. Chen J. Tan J. et al.Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth.Mol Cancer Ther. 2011; 10: 2298-2308Crossref PubMed Scopus (912) Google Scholar High level of phosphorylated c-MET has been associated with resistance to sorafenib, and blockade of c-MET by cabozantinib was shown to overcome this in tissue models.36Xiang Q. Chen W. Ren M. et