U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Hoshida Y, editor. Hepatocellular Carcinoma: Translational Precision Medicine Approaches [Internet]. Cham (CH): Humana Press; 2019. doi: 10.1007/978-3-030-21540-8_11

Cover of Hepatocellular Carcinoma

Hepatocellular Carcinoma: Translational Precision Medicine Approaches [Internet].

Show details

Chapter 11Molecular-Targeted Therapies in Hepatocellular Carcinoma

, , , and .

Author Information and Affiliations

Published online: August 6, 2019.

The management of patients with advanced-stage hepatocellular carcinoma (HCC) has changed dramatically over the past year. Partial hepatectomy, liver transplantation, ablation, radiation therapy, and embolization procedures remain important interventions for localized HCC, whereas systemic therapy is the cornerstone of therapy for patients with extrahepatic disease. Since 2017, several agents, including regorafenib, lenvatinib, cabozantinib, ramucirumab, nivolumab, and pembrolizumab, have been approved or are likely approved as first- and second-line therapies by Food and Drug Administration (FDA) for systemic treatment of advanced-stage HCC. In this chapter, we overview the molecular mechanisms underlying HCC and how improved understanding of these pathways has helped the development of targeted therapies. We also discuss the value of these molecular-targeted therapeutic agents, safety profile, and their impact on personalization of HCC therapy.

Keywords:

Hepatocellular carcinoma, Sorafenib, Nivolumab, Regorafenib, Lenvatinib, Targeted therapy

Introduction

Liver cancers are expected to account for approximately 42, 000 new cases and 30,000 deaths in 2018 in the United States, 90% of which are hepatocellular carcinoma (HCC) [1]. The incidence of the disease has almost tripled since mid-1980s and HCC-related cancer deaths are increasing at a rapid pace as compared to other cancer types. Early-stage HCC (stage 1 and some stage II cancers) is generally treated with surgery and in selected cases with liver transplantation. In contrast, the majority of patients present with unresectable, advanced HCC, and require locoregional therapy (ablation, arterially directed therapies, or external beam radiation therapy) or systemic treatment depending on the extent of the disease and their functional status [2]. Systemic treatment options typically include molecular-targeted therapy with sorafenib or enrollment into clinical trials. Sorafenib had been the only FDA-approved therapy for systemic treatment of advanced HCC for almost a decade. More recently, other systemic therapies such as regorafenib and nivolumab have been approved as second-line treatment for patients with HCC who progress on sorafenib [2]. In addition, other molecular targeted agents such as lenvatinib, pembrolizumab, and cabozantinib have shown promising results in recent clinical trials [3–6]. With broader range of systemic therapies becoming available, the treatment of patients with HCC now involves a decision-making process with consideration for the magnitude of the beneficial effects of the therapeutic agent as well as other factors including adverse events, patient baseline functional status, comorbidities, and Child-Pugh score. Clinical trials with new active agents are in progress, and many of these trials focused on targeted therapies and immunotherapies with the intense interest in developing novel, more effective, and less toxic agents. The current chapter details about the molecular pathogenesis of HCC, targeted therapies, and newer systemic therapies on the horizon in the management of HCC. For a better understanding of molecular-targeted therapies for HCC, we detailed some of the key signaling pathway alterations that play a significant role in the pathogenesis of HCC. A detailed description of immunotherapy and related pathways in the management of advanced HCC in described elsewhere in Chap. 12.

Molecular Therapeutic Targets in HCC

Activation of receptor tyrosine kinase (RTK) by inducing the RAS-MAPK/ERK and PI3K-Akt kinase signaling pathways is observed generally in less than 5% of HCC tumors [7]. Phosphorylation of RTKs such as vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), hepatocyte growth factor receptor (HGFR)/c-MET, and the stem cell growth factor receptor (c-kit) leads to activation of the MAPK and PI3K pathways. This activation of MAPK/ERK pathway triggers the proto-oncogene cFos and transcription factor AP-1/c-Jun, thereby leading to tumor cell proliferation [8]. In approximately half of the HCC cases, activation of PI3K-AKT kinase pathway via insulin/insulin-like growth factor (IGF) receptors result in mTOR activation, thereby promoting the carcinogenesis [8]. Loss of function of PTEN, a tumor suppressor gene by mutation or epigenetic silencing, can also lead to the activation of PI3K-AKT kinase pathway [7]. In addition, polymorphism of EGF gene results in the triggering of EGFR pathway, thereby leading to HCC initiation. A case-control study has shown that hepatic expression-associated EGF gene polymorphism (SNP rs44449030) (G/G versus A/A) in cirrhotic patients results in fourfold increase in the risk of HCC [9].

FGFR pathway is another RTK pathway that has been implicated in the pathogenesis of HCC. The ligands of FGF family interact with four FGF receptors (FGFR1–4). Among these four subtypes of receptors, FGFR4 is the most abundant receptor expressed in hepatocytes. The ligand, FGF19, binds to FGFR4 and plays an important role in regulating bile acid synthesis and hepatocyte proliferation. The activation of this FGF19-FGFR4 pathway activation may play a key role in a proportion of HCCs, and this pathway is a potential therapeutic target [8]. A phase I clinical trial that evaluated a highly selective small molecular FGFR4 inhibitor showed promising results in advanced HCC tumors that harbored FGF19-activated tumors. The maximum tolerated dose was 600 mg. This study opened new therapeutic approach in the management of advanced HCC that express FGF19.

Another RTK pathway implicated in the pathogenesis of HCC is the HGF (ligand)/c-MET pathway. Activation of c-MET triggers the stimulation of downstream effector molecules, PI3K and ERK. A subgroup analysis in patients in a randomized trial evaluating sorafenib revealed an increased expression of HGF levels in patients who did not respond to sorafenib [10]. These high HGF levels correlated with poor prognosis. It is postulated that MET activation was associated with vascular invasion and poor prognosis in human HCC [10].

HCC is a highly vascular tumor and neo-angiogenesis is a prominent feature, with the hepatic artery as the major source of its blood supply. VEGF and other vascular growth factors (PDGF, FGF) play a prominent role in promoting and sustaining neo-angiogenesis in HCC [11]. This neo-angiogenesis from pre-existing vasculature is a fundamental process of the supply of oxygen and nutrients to the expanding tumor mass. The increased expression of both VEGF and its receptor (VEGFR) is frequently seen in HCC, and VEGF level correlates with microvessel density, angiogenic activity, tumor progression, metastasis, postoperative recurrence, and poor prognosis [12]. A cross talk between VEGF and FGF also plays a key role in the angiogenesis of HCC. The expression of FGFR, VEGFR and PDGFR, and their ligands are increased in HCC, and high expression of FGFR is also related to the capsular invasion of neoplastic cells. In addition, PDGF overexpression has been linked to the increased metastatic potential of HCC. It is important to note that the increased VEGF expression in the tumor mass often leads to disorganized and immature neo-vascularization. This immature neo-angiogenesis can lead to focal areas of tumor hypoxia in the rapidly expanding tumor mass. This hypoxic environment leads to the stimulation of growth factors such as hypoxia-inducible factor (HIF)-1 and 2 that are further shown to cause local tumor advancement and metastases, especially by increasing the expression of SERPINB3 [13]. The increased expression of HIFs can potentially lead to failure of localized therapies such as trans-arterial embolization and poor prognosis after the treatment [8]. HIF-2 alpha antagonists that showed promising results in renal cell carcinoma may be a potential option in HCC by targeting the HIF pathway [14].

Other potential trigger of the carcinogenic tyrosine kinase pathway is the effects on the affinity of heparan sulfate for heparan sulfate-binding receptor tyrosine ligands. Many RTKs use heparan sulfate as a co-receptor, and a pair of heparan sulfate sulfatases, SULF1 and SULF2, have been shown to modulate HCC carcinogenesis and tumorigenesis [15]. In addition, increased expression of HDAC2 gene that is involved in histone modification was found to be expressed more in HCC patients. HDAC2 gene regulates histone deacetylases (HDACs), chromatin-modifying enzymes that are involved in epigenetic regulation of cell cycle, differentiation, and apoptosis.

The JAK-STAT signaling pathway consists of three main components: a cell surface receptor, a Janus kinase (JAK), and two signal transducer and activator of transcription (STAT) proteins [16]. A variety of interleukins, cytokines, and growth factors can trigger STATs via tyrosine phosphorylation by JAKs. Dysregulation of JAK-STAT cascade can lead to cell migration and differentiation, thereby causing cancers and immunodeficiency syndromes. This activation of JAK-STAT cascade has been implicated in the carcinogenesis of HCC [17].

Genetic mutations that alter the WNT/β-catenin signaling pathway have been implicated in the carcinogenesis in about half of the HCC cases [8]. Though multiple mechanisms that activate Wnt pathway are proposed, the most common mutations acting on the WNT/β-catenin signaling pathway are acting mutations in CTNNB1 (results in the stabilization of β-catenin), inactivation of APC tumor suppressor gene, and mutations in AXIN1 and AXIN 2 (negative regulators of the Wnt pathway) [18]. The molecular pathogenesis in the HCC is thought to be different in different etiological entities. For example, activation of canonical WNT signaling pathway without CTNNB1 mutations is preferentially seen in HCC tumors with more aggressive molecular and clinical features [19].

Transforming growth factor (TGF)-β pathway dysregulation, which can be caused by genetic and other types of aberrations, has been implicated in molecular pathogenesis in HCC [20]. TGF-β signaling has been shown to play a critical role in cellular proliferation, apoptosis, differentiation, motility, lineage specificity, and stem cell homeostasis. TGF-β receptor inhibitor, Galunisertib, has been tested in clinical trials as single agent or in combination with immune checkpoint inhibitors (ClinicalTrials.gov) [21].

Therapeutic intervention toward some of these pathways is now feasible by using clinically developed and/or FDA-approved agents as summarized below.

Clinically Tested Molecular-Targeted Agents for HCC

Multiple small molecule inhibitors, therapeutic antibodies, and immune checkpoint inhibitors have been evaluated in clinical trials, some of which have been approved or are soon to be approved as the first- and second-line therapies for advanced HCC (Table 11.1). Several agents such as sunitinib and tivantinib failed to meet the primary endpoint in “all-comer” clinical trials without prior patient selection. These agents may be found still beneficial in a subset of HCC patients if predictive biomarkers of response are identified.

Table 11.1

Table 11.1

Molecular-targeted agents approved or soon-to-be-approved for advanced HCC treatment

Sorafenib

Sorafenib, a multi-kinase (serine, threonine, and tyrosine kinases) inhibitor was the first agent that showed benefit in prolonging median overall survival (OS) in advanced HCC. The drug primarily acts by targeting receptor tyrosine kinase pathway by blocking rapidly accelerated fibrosarcoma (RAF) kinases; VEGFR1, 2, and 3; PDGFR; and c-kit. Apart from blocking RTK pathway, other potential mechanisms of action have also been postulated. A study by Tai et al. has shown that sorafenib also acts by targeting the STAT3 pathway [22]. The drug also targets matrix metalloproteinase-2 and Ki-67 expression via simultaneous upregulation of p53 and suppression of transcription factor, forkhead box M1 (FOXM1) [23]. Blocking of FOXM1 leads to cell-cycle arrest by causing mitotic spindle defects and chromosome disaggregation. Sorafenib is also shown to target IGF1-mediated neoplastic cell proliferation and macrophage-mediated tumor cell growth [24].

Though the mechanisms underlying the sorafenib effect are not fully understood, the drug showed prolonging median OS patients with advanced, metastatic HCC in two randomized phase III trials (SHARP and Asia Pacific Trial) [25]. SHARP trial was a multicenter randomized placebo control study involving 602 treatment-naïve advanced HCC patients. Study subjects were randomized to receive sorafenib 400 mg twice daily or placebo. The subjects in the sorafenib arm had a better median OS as compared to that of placebo arm (10.7 vs 7.9 months) (hazard ratio [HR] =0.69 [95% CI = 0.55–0.87]; p = 0.001). Time to radiologic progression of the disease was improved by 3 months in sorafenib arm (5.5 vs 2.8 months, p < 0.001). Similar results with sorafenib were seen in the Asia-Pacific study (median OS: 6.5 vs. 4.2 months, HR = 0.68 [95% CI = 0.53–0.93], p = 0.01; median time to progression: 2.8 vs 1.4 months, HR 0.57 [95% CI = 0.42–0.79], p = 0.0005). The side effect profile of sorafenib was similar in both the trials, and most common adverse events noted were weight loss, diarrhea, hand-foot skin reaction, and hypophosphatemia. Overall objective response rates (ORRs) were low, occurring in 1% of the patients, and none of the patients achieved complete response in both the trials. Both the studies included patients with good performance status of ECOG 0 or 1 (90%) and good liver function (95% of patients in sorafenib group were Child-Pugh class A and 5% were class B). Nonetheless, given the prolonged OS in sorafenib group, the FDA approved this medication for advanced metastatic HCC. The safety profile of sorafenib is further evaluated in a phase IV Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafenib (GIDEON) trial to evaluate safety profile and drug efficacy in various patient subgroups [26].

Sorafenib was also evaluated in a phase II double-blinded randomized trial in combination with doxorubicin involving 96 advanced HCC survivors. The study subjects were randomized to doxorubicin alone or in combination with sorafenib. The combination group showed significant improvement in time to progression (6.4 vs. 2.8 months; p = 0.02), progression-free survival (PFS) (6 vs. 2.7 months; p = 0.006), and median OS (13.7 vs. 6.7 months; p = 0.006) [27]. However, these positive results were not replicated in phase III trial and the study was suspended prematurely due to increased toxicity and unlikely advantages of the combination regimen [28].

Sorafenib was also evaluated in combination with local therapies such as transarterial chemoembolization (TACE). TACE is generally reserved as a palliative treatment option for patients with locally advanced and unresectable HCC. TACE showed improved survival as compared to that of control arm that received symptomatic management only. Wang et al. showed that there is an increased expression of VEGF and PDGF after TACE procedure, which may contribute to tumor neo-angiogenesis and progression [29]. Phase III trials of combining sorafenib to TACE, TACTICS (in Japan) and TACE-2 (in UK), have been recently conducted [30–33]. In the TACTICS trial, the treatment was well tolerated and resulted in significant improvement in time to tumor progression (24.1 vs. 13.5 months; p = 0.004) and PFS (25.2 vs. 13.5 months; p = 0.006). On the other hand, TACE-2 trial showed no significant improvement in PFS (326 vs. 320 days; HR = 1.01; 95% CI = 0.78–1.30; p = 0.94) and OS (631 vs. 598 days; HR = 0.91 [95% CI 0.67–1.24]; p = 0.57) by adding sorafenib to TACE. Sorafenib was also evaluated in the adjuvant setting after surgical resection in phase II and III trails, which showed mixed results. A recent meta-analysis reported no significant benefit of using sorafenib as postsurgical adjuvant therapy [34].

Regorafenib

Regorafenib, structurally related to sorafenib, was approved as a second-line agent for the use in HCC patients whose disease progressed while on sorafenib. Regorafenib is also multikinase inhibitor blocking the tyrosine kinase pathway, thereby targeting the angiogenesis (VEGFR1, 2 and 3), tumor environment (PDGFR and FGFR), and oncogenesis (c-kit, RET, and RAF). Regorafenib was evaluated in an open-label, phase II trial involving 36 HCC patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function (Child-Pugh class A) who progressed on sorafenib therapy. Median time to progression (TTP) was 4.3 months and median OS was 13.8 months. Most common adverse events noted were hand-foot syndrome, fatigue, hypertension, diarrhea, and hypothyroidism. The drug was further evaluated in a phase III RESORCE trial that randomized 573 patients with HCC into best supportive care plus either regorafenib 160 mg once daily (3 weeks on/1 week off) arm or placebo arm (n = 194) [35]. All study subjects were on prior sorafenib therapy with a documented radiological progression. The regorafenib group showed significant improvement in median OS (10.6 vs. 7.8 months; HR = 0.63; 95% CI: 0.50–0.79; p < 0.0001), median TTP (3.2 vs. 1.5 months; HR = 0.44; 95% CI = 0.036–0.55; p < 0.001), and PFS (3.1 vs. 1.5 months; HR = 0.46; 95% CI = 0.37–0.56; p < 0.001) [35]. Patients in regorafenib arm had a better overall response rate (10.6% vs. 4.1%; p = 0.005) and overall disease control rate (65.2% vs. 36.1%; p < 0.001) as compared to that of placebo. Most common adverse events noted in regorafenib group were hypertension, hand-foot skin reaction, fatigue, and diarrhea.

Lenvatinib

Lenvatinib is a small molecule inhibitor of multiple kinases, VEGFR1–3, FGFR1–4, PDGFR, RET, and c-kit, which was approved as a first-line therapy for advanced HCC. In a phase II trial that involved 46 metastatic HCC patients, lenvatinib-treated patients had a median OS of 18.7 months with a median TTP of 12.8 months. Though none of the patients demonstrated complete response, 47% of the patients had stable disease, and subgroup analyses showed similar promising results. Lenvatinib was subsequently evaluated in an open-label noninferiority phase III REFLECT trial [36]. Median PFS (7.4 vs. 3.7 months; HR = 0.66; 95% CI = 0.57–0.77; p < 0.0001) and median TTP (8.9 vs. 3.7 months; HR = 0.63; 95% CI = 0.53–0.73; p < 0.0001) favored lenvatinib over sorafenib. Lenvatinib was demonstrated to be noninferior to sorafenib in terms of median OS (13.6 vs. 12.3 months; HR = 0.92; 95% CI = 0.79–1.06), which was the primary endpoint. Most common adverse events noted in the lenvatinib arm were hypertension (41–76%), hand-foot erythrodysesthesia syndrome (65%), proteinuria (61%), diarrhea (39%), and fatigue (30–61%). Of note, 57% of the patients experienced severer adverse events (grade 3 and above) with 18% of the patients reporting treatment-related serious adverse events.

Cabozantinib

Cabozantinib is an oral kinase pathway inhibitor, targeting c-MET, VEGFR2, Axl, and RET, which has been evaluated in clinical trials, enrolling advanced HCC patients [4, 6]. In a phase II trial that evaluated cabozantinib in 41 advanced HCC patients, partial response or stable disease was observed in 66% of the patients. Median PFS in cabozantinib and placebo groups were 2.5 and 1.4 months, respectively (difference was not statistically significant). In a randomized double-blind placebo-controlled phase III CELESTIAL trial involving 707 advanced HCC patients (2:1 randomization), cabozantinib was associated with 24% reduced risk of dying as compared to that of placebo group, and median OS improved by 2.2 months (10.2 vs. 8.0 months; HR = 0.76; 95% CI = 0.63–0.92; p = 0.0049) [6]. Cabozantinib was also associated with a better median PFS (5.2 vs. 1.9 months; HR: 0.44, 95% CI = 0.36–0.52; p < 0.0001). Most common adverse events noted in cabozantinib group were diarrhea (20%), palmar-plantar erythrodysesthesia (15%), and thrombocytopenia (15%). Grade 5 toxicities (hepatic failure, esophagobronchial fistula, portal vein thrombosis, upper gastrointestinal hemorrhage, pulmonary embolism, and hepatorenal syndrome) were seen in six patients who received cabozantinib.

Ramucirumab

Ramucirumab is a human IgG1 monoclonal antibody against VEGFR2 that has shown encouraging results in advanced HCC by targeting endothelial cell proliferation and migration. In a phase II trial involving 42 advanced HCC patients, ramucirumab was associated with a median overall survival of 12 months with 9.5% OS rate. Given these encouraging results, the drug was evaluated in a randomized placebo control phase III REACH trial, enrolling unselected 643 patients advanced HCC patients [37]. A potential OS benefit was suggested in patients with baseline AFP levels of 400 ng/mL or more and Child-Pugh score of 5 (HR = 0.61; 95% CI = 0.43–0.87; p = 0.01) and Child-Pugh score of 6 (HR = 0.64; 95% CI = 0.42–0.98; p = 0.04) in posthoc subgroup analyses. To validate the finding, a phase III REACH-2 study was conducted by enrolling 292 advanced HCC patients with baseline AFP 400 ng/mL or greater and Child-Pugh class A who progressed on or were intolerant to sorafenib (NCT02435433) [38]. Patients were randomized (2:1) to receive ramucirumab 8 mg/kg i.v. or placebo. Ramucirumab treatment significantly improved median OS (8.5 vs. 7.3 months; HR = 0.71; 95% CI = 0.53–0.95; p = 0.02) and PFS (2.8 vs. 1.6 months; HR = 0.45; 95% CI = 0.34–0.60; p < 0.0001). Risk of death was reduced by 29%. ORRs were 4.6% and 1.1% (p = 0.12) and disease control rates (ORR + stable disease) were 59.9% and 38.9% (p = 0.0006) in ramucirumab and placebo arms, respectively. Adverse events (grade 3 and above) occurred include hypertension (12.2% in ramucirumab and 5.3% in placebo) and hyponatremia (5.6% in ramucirumab and 0% in placebo). REACH-2 is the first positive phase III study conducted in biomarker-selected patients with HCC.

Sunitinib

Sunitinib is an oral multikinase inhibitor that targets VEGFR1–3, PDGFR, c-kit, and RET. In phase II trials in advanced HCC patients, ORRs were 2.7–12% and median Oss were 5.8–9.8 months [39]. With the high dose of sunitinib (50 mg daily, 4 weeks on and 2 weeks off) in these trials, high incidences of grade 3 or 4 toxicities, such as thrombocytopenia, neutropenia, asthenia, hand-foot syndrome, and fatal treatment-related events, were noted. In a phase III trial, reduced dose of sunitinib (37.5 mg daily for 4 weeks on and 2 weeks off) was compared to sorafenib 400 mg twice daily in 1074 Child-Pugh class A patients with advanced HCC [40]. The trial was terminated prematurely due to drug-related toxicity and inferior outcomes in sunitinib arm. Patients in the sunitinib arm had a shorter median OS compared to that of sorafenib arm (7.9 vs. 10.2 months; HR = 1.30; 95% CI = 1.13–1.30; p = 0.001).

Tivantinib

A small-molecule compound, tivantinib, has been tested as a c-Met inhibitor for second-line treatment of advanced HCC in a phase II trial, in which positive c-Met immunostaining was associated with extended TTP in a posthoc subgroup analysis (2.7 vs. 1.4 months; HR = 0.43; 95% CI = 0.19–0.97; p = 0.03) [41]. In the subsequent phase III METIV-HCC trial enrolling c-Met-positive inoperable HCC patients, the prognostic benefit was not validated [42]. More recent studies suggest that tivantinib is not a specific c-Met inhibitor [43].

Bevacizumab

Bevacizumab, a humanized monoclonal antibody targeting VEGF, elicits antiangiogenic effect and has been evaluated in advanced HCC patients either as a monotherapy or in combination with other agents, including erlotinib, gemcitabine with oxaliplatin, and capecitabine with or without oxaliplatin [44]. As a single agent, it showed ORR of 13% with a median OS of 12.4 months [45]. As a combination therapy with gemcitabine and oxaliplatin, the drug showed an ORR of 20% and PFS of 9.6 months [44]. Most trials of bevacizumab reported median PFS between 5.3 and 9 months and OS between 5.9 and 13.7 months with the disease control rate ranging from 51% to 77%. Most common grade 3/4 adverse events noted were increased liver enzymes (13%), fatigue (12%), high blood pressure (10%), diarrhea (8%), and neutropenia (5%). Trials of bevacizumab combined with other agents are currently under investigation in HCC (ClinicalTrials.gov).

Other Tyrosine Kinase Inhibitors

Other tyrosine kinase pathway inhibitors have been evaluated in advanced HCC patients with no positive results. Cediranib, a VEGFR, c-kit, and PDGFR inhibitor, showed no clinically significant improvement in response to therapy with a high incidence of adverse events [46]. Linifanib is an inhibitor of VEGFR and PDGFR, and has shown promising results in phase I and II trials, although it failed to show superiority to sorafenib in a phase III randomized clinical trial [47]. Moreover, linifanib was not tolerated well with high incidence of grade 3/4 adverse events leading to its discontinuation to be compared with sorafenib [47]. Similar findings were seen in phase II and III clinical trials of brivanib, an inhibitor of VEGFR and FGFR, in patients with advanced HCC [48]. In phase III randomized sorafenib-controlled clinical trial, brivanib was found to be noninferior to sorafenib but was associated with high degree of toxicities with less tolerability profile compared to sorafenib [48]. Most common adverse events noted were hypertension, hyponatremia, and fatigue. Similarly, orantinib, an inhibitor of VEGFR2, PDGFR, and FGFR, yielded an ORR of 8.6% in a phase II clinical trial involving metastatic HCC patients [49]. The drug did not show any benefit in phase III randomized placebo-controlled trial when added as an adjuvant therapy to TACE [50].

Everolimus

Everolimus is an inhibitor of mechanistic target of rapamycin (mTOR). Despite encouraging prolongation of median OS (7.7 vs. 5.7 months) and PFS (3.7 vs. 1.9 months) compared to placebo in a phase II clinical trial [51], subsequent phase III EVOLVE I trial, enrolling 546 advanced HCC patients who did not tolerate or progressed on sorafenib, failed to validate the results for median OS (7.6 vs. 7.3 months for treatment and placebo arms, respectively) and TTP (3 vs. 2.6 months for treatment and placebo arms, respectively). Everolimus was also tested as combination therapy with sorafenib compared with sorafenib alone in a randomized phase II trial. The trial did not show any additional benefit over sorafenib monotherapy in terms of ORR (0% vs. 10%) and PFS (68% vs. 70%) with increased incidence of adverse events [52].

Future Directions

HCC is the most common type of liver cancer, and its incidence has almost tripled since 1980, and the management of advanced HCC will remain the major clinical challenge [53]. Recent approval of multiple systemic therapies has opened the avenue toward tailored medical treatment of advanced HCC according to associated specific molecular aberrations. Molecular targeted agents, which failed to demonstrate clinical benefit in unselected “all-comer” trials may still have value in a subset of patients if predictive biomarkers of response are identified. For biomarker exploration, acquisition of biospecimens, especially tissue, will be critical and inter- and intratumor heterogeneity of molecular aberrations (covered in Chap. 14) need to be addressed to elucidate clinically actionable information that guide the systemic therapies. Circulating biomarkers (covered in Chap. 7) will enable flexible clinical application of such predictive biomarkers of drug response. Given the complex molecular dysregulations implicated in HCC pathogenesis, combination therapies especially with immune-oncology agents may enable improved management of the patients with advanced HCC.

References

1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30. https://doi​.org/10.3322/caac.21387. [PubMed: 28055103] [CrossRef]
2.
(NCCN) NCCN. NNCN Guidelines version 1.2018 Hepatocellular carcinoma. 2017. https://www​.nccn.org​/professionals/physician_gls​/pdf/hepatobiliary.pdf. Accessed 24 Feb 2018.
3.
Cheng A-L, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2017;35(15_suppl):4001. https://doi​.org/10.1200/JCO​.2017.35.15_suppl.4001. [CrossRef]
4.
Kelley RK, Verslype C, Cohn AL, Yang TS, Su WC, Burris H, et al. Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study. Ann Oncol. 2017;28(3):528–34. https://doi​.org/10.1093/annonc/mdw651. [PMC free article: PMC5391701] [PubMed: 28426123] [CrossRef]
5.
Finn RS, Chan SL, Zhu AX, Knox JJ, Cheng A-L, Siegel AB, et al. KEYNOTE-240: randomized phase III study of pembrolizumab versus best supportive care for second-line advanced hepatocellular carcinoma. J Clin Oncol. 2017;35(4_suppl):TPS503-TPS. https://doi​.org/10.1200/JCO​.2017.35.4_suppl.TPS503. [CrossRef]
6.
Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379(1):54–63. https://doi​.org/10.1056/NEJMoa1717002. [PMC free article: PMC7523244] [PubMed: 29972759] [CrossRef]
7.
Shibata T, Arai Y, Totoki Y. Molecular genomic landscapes of hepatobiliary cancer. Cancer Sci. 2018;109(5):1282–91. https://doi​.org/10.1111/cas.13582. [PMC free article: PMC5980207] [PubMed: 29573058] [CrossRef]
8.
Dhanasekaran R, Bandoh S, Roberts LR. Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances. F1000Res. 2016;5:F1000 Faculty Rev-879. https://doi​.org/10.12688/f1000research​.6946.1. [PMC free article: PMC4870992] [PubMed: 27239288] [CrossRef]
9.
Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T, Chung RT, et al. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA. 2008;299(1):53–60. https://doi​.org/10.1001/jama.2007.65. [PubMed: 18167406] [CrossRef]
10.
Goyal L, Muzumdar MD, Zhu AX. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin Cancer Res. 2013;19(9):2310–8. https://doi​.org/10.1158/1078-0432​.CCR-12-2791. [PMC free article: PMC4583193] [PubMed: 23388504] [CrossRef]
11.
Bocca C, Novo E, Miglietta A, Parola M. Angiogenesis and fibrogenesis in chronic liver diseases. Cell Mol Gastroenterol Hepatol. 2015;1(5):477–88. https://doi​.org/10.1016/j​.jcmgh.2015.06.011. [PMC free article: PMC5301407] [PubMed: 28210697] [CrossRef]
12.
Dai L, Peng XX, Tan EM, Zhang JY. Tumor-associated antigen CAPERalpha and microvessel density in hepatocellular carcinoma. Oncotarget. 2016;7(13):16985–95. https://doi​.org/10.18632/oncotarget.7707. [PMC free article: PMC4941365] [PubMed: 26934653] [CrossRef]
13.
Cannito S, Turato C, Paternostro C, Biasiolo A, Colombatto S, Cambieri I, et al. Hypoxia up-regulates SERPINB3 through HIF-2alpha in human liver cancer cells. Oncotarget. 2015;6(4):2206–21. https://doi​.org/10.18632/oncotarget.2943. [PMC free article: PMC4385846] [PubMed: 25544768] [CrossRef]
14.
Tella SH, Taieb D, Pacak K. HIF-2alpha: Achilles’ heel of pseudohypoxic subtype paraganglioma and other related conditions. Eur J Cancer. 2017;86:1–4. https://doi​.org/10.1016/j​.ejca.2017.08.023. [PMC free article: PMC6287501] [PubMed: 28946040] [CrossRef]
15.
Lai JP, Thompson JR, Sandhu DS, Roberts LR. Heparin-degrading sulfatases in hepatocellular carcinoma: roles in pathogenesis and therapy targets. Future Oncol. 2008;4(6):803–14. https://doi​.org/10.2217/14796694.4.6.803. [PMC free article: PMC3042146] [PubMed: 19086847] [CrossRef]
16.
Aaronson DS, Horvath CM. A road map for those who don’t know JAK-STAT. Science. 2002;296(5573):1653–5. https://doi​.org/10.1126/science.1071545. [PubMed: 12040185] [CrossRef]
17.
Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006;130(4):1117–28. https://doi​.org/10.1053/j​.gastro.2006.01.006. [PubMed: 16618406] [CrossRef]
18.
Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol. 2013;59(5):1107–17. https://doi​.org/10.1016/j​.jhep.2013.07.001. [PubMed: 23835194] [CrossRef]
19.
Goossens N, Sun X, Hoshida Y. Molecular classification of hepatocellular carcinoma: potential therapeutic implications. Hepat Oncol. 2015;2(4):371–9. https://doi​.org/10.2217/hep.15.26. [PMC free article: PMC4662420] [PubMed: 26617981] [CrossRef]
20.
Rao S, Mishra L. Targeting TGF-beta signaling in liver cancer. Hepatology. 2018; https://doi​.org/10.1002/hep.30426. [CrossRef]
21.
Fabregat I, Caballero-Diaz D. Transforming growth factor-beta-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front Oncol. 2018;8:357. https://doi​.org/10.3389/fonc.2018.00357. [PMC free article: PMC6139328] [PubMed: 30250825] [CrossRef]
22.
Tai WT, Cheng AL, Shiau CW, Huang HP, Huang JW, Chen PJ, et al. Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. J Hepatol. 2011;55(5):1041–8. https://doi​.org/10.1016/j​.jhep.2011.01.047. [PubMed: 21354226] [CrossRef]
23.
Wei JC, Meng FD, Qu K, Wang ZX, Wu QF, Zhang LQ, et al. Sorafenib inhibits proliferation and invasion of human hepatocellular carcinoma cells via up-regulation of p53 and suppressing FoxM1. Acta Pharmacol Sin. 2015;36(2):241–51. https://doi​.org/10.1038/aps.2014.122. [PMC free article: PMC4326788] [PubMed: 25557114] [CrossRef]
24.
Sprinzl MF, Puschnik A, Schlitter AM, Schad A, Ackermann K, Esposito I, et al. Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1 secretion. J Hepatol. 2015;62(4):863–70. https://doi​.org/10.1016/j​.jhep.2014.11.011. [PubMed: 25463538] [CrossRef]
25.
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, 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(1):25–34. https://doi​.org/10.1016​/S1470-2045(08)70285-7. [PubMed: 19095497] [CrossRef]
26.
Lencioni R, Kudo M, Ye SL, Bronowicki JP, Chen XP, Dagher L, et al. GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and of its treatment with sorafeNib): second interim analysis. Int J Clin Pract. 2014;68(5):609–17. https://doi​.org/10.1111/ijcp.12352. [PMC free article: PMC4265239] [PubMed: 24283303] [CrossRef]
27.
Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010;304(19):2154–60. https://doi​.org/10.1001/jama.2010.1672. [PubMed: 21081728] [CrossRef]
28.
Abou-Alfa GK, Niedzwieski D, Knox JJ, Kaubisch A, Posey J, Tan BR, et al. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). J Clin Oncol. 2016;34(4_suppl):192. https://doi​.org/10.1200/jco​.2016.34.4_suppl.192. [CrossRef]
29.
Wang B, Xu H, Gao ZQ, Ning HF, Sun YQ, Cao GW. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol. 2008;49(5):523–9. https://doi​.org/10.1080​/02841850801958890. [PubMed: 18568538] [CrossRef]
30.
Chao Y, Chung YH, Han G, Yoon JH, Yang J, Wang J, et al. The combination of transcatheter arterial chemoembolization and sorafenib is well tolerated and effective in Asian patients with hepatocellular carcinoma: final results of the START trial. Int J Cancer. 2015;136(6):1458–67. https://doi​.org/10.1002/ijc.29126. [PubMed: 25099027] [CrossRef]
31.
Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, Izumi N, Yamasaki T, Nojiri S, TACTICS trial group. Randomized, open label, multicenter, phase II trial comparing transarterial chemoembolization (TACE) plus sorafenib with TACE alone in patients with hepatocellular carcinoma (HCC): TACTICS trial. ASCO, ASCO Gastrointestinal symposium. J Clin Oncol. 2018;36(suppl 4S; abstr 206):2018. Accessed 25 Feb 2018.
32.
Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2(8):565–75. https://doi​.org/10.1016​/S2468-1253(17)30156-5. [PubMed: 28648803] [CrossRef]
33.
de Jesus VHF, Dettino ALA. Update on hepatocellular carcinoma from the 2018 Gastrointestinal Cancer Symposium (ASCO GI). J Hepatocell Carcinoma. 2018;5:87–90. https://doi​.org/10.2147/JHC.S171396. [PMC free article: PMC6174912] [PubMed: 30324097] [CrossRef]
34.
Shang J, Xu S, Zhang J, Ran X, Bai L, Tang H. Efficacy of sorafenib in patients with hepatocellular carcinoma after resection: a meta-analysis. Oncotarget. 2017;8(65):109723–31. https://doi​.org/10.18632/oncotarget​.21299. [PMC free article: PMC5752555] [PubMed: 29312642] [CrossRef]
35.
Bruix J, Qin S, Merle P, Granito A, Huang Y-H, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 389(10064):56–66. https://doi​.org/10.1016​/S0140-6736(16)32453-9. [PubMed: 27932229] [CrossRef]
36.
Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. https://doi​.org/10.1016​/S0140-6736(18)30207-1. [PubMed: 29433850] [CrossRef]
37.
Zhu AX, Baron AD, Malfertheiner P, Kudo M, Kawazoe S, Pezet D, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: analysis of REACH trial results by Child-Pugh score. JAMA Oncol. 2016; https://doi​.org/10.1001/jamaoncol​.2016.4115. [PubMed: 27657674] [CrossRef]
38.
Zhu AX, Kang Y, Yen C, Finn RS, Galle PR, Llovet JM, et al. REACH-2: a randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. J Clin Oncol. 2018;36((15) supp)
39.
Barone C, Basso M, Biolato M, Pompili M, Rufini V, Miele L, et al. A phase II study of sunitinib in advanced hepatocellular carcinoma. Dig Liver Dis. 2013;45(8):692–8. https://doi​.org/10.1016/j​.dld.2013.01.002. [PubMed: 23410734] [CrossRef]
40.
Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31(32):4067–75. https://doi​.org/10.1200/JCO.2012.45.8372. [PubMed: 24081937] [CrossRef]
41.
Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, et al. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol. 2013;14(1):55–63. https://doi​.org/10.1016​/S1470-2045(12)70490-4. [PubMed: 23182627] [CrossRef]
42.
Rimassa L, Assenat E, Peck-Radosavljevic M, Pracht M, Zagonel V, Mathurin P, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018;19(5):682–93. https://doi​.org/10.1016​/S1470-2045(18)30146-3. [PubMed: 29625879] [CrossRef]
43.
Rebouissou S, La Bella T, Rekik S, Imbeaud S, Calatayud AL, Rohr-Udilova N, et al. Proliferation markers are associated with MET expression in hepatocellular carcinoma and predict tivantinib sensitivity in vitro. Clin Cancer Res. 2017;23(15):4364–75. https://doi​.org/10.1158/1078-0432​.CCR-16-3118. [PubMed: 28246274] [CrossRef]
44.
Zhu AX, Blaszkowsky LS, Ryan DP, Clark JW, Muzikansky A, Horgan K, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24(12):1898–903. https://doi​.org/10.1200/jco.2005.04.9130. [PubMed: 16622265] [CrossRef]
45.
Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008;26(18):2992–8. https://doi​.org/10.1200/jco.2007.15.9947. [PMC free article: PMC3635806] [PubMed: 18565886] [CrossRef]
46.
Zhu AX, Ancukiewicz M, Supko JG, Sahani DV, Blaszkowsky LS, Meyerhardt JA, et al. Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study. Clin Cancer Res. 2013;19(6):1557–66. https://doi​.org/10.1158/1078-0432​.ccr-12-3041. [PMC free article: PMC3609423] [PubMed: 23362324] [CrossRef]
47.
Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33(2):172–9. https://doi​.org/10.1200/JCO.2013.54.3298. [PMC free article: PMC4279237] [PubMed: 25488963] [CrossRef]
48.
Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31(28):3517–24. https://doi​.org/10.1200/jco.2012.48.4410. [PubMed: 23980084] [CrossRef]
49.
Kanai F, Yoshida H, Tateishi R, Sato S, Kawabe T, Obi S, et al. A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2011;67(2):315–24. https://doi​.org/10.1007​/s00280-010-1320-2. [PubMed: 20390419] [CrossRef]
50.
Kudo M, Cheng A-L, Park J-W, Park JH, Liang P-C, Hidaka H, et al. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet Gastroenterol Hepatol. 3(1):37–46. https://doi​.org/10.1016​/S2468-1253(17)30290-X. [PubMed: 28988687] [CrossRef]
51.
Shiah HS, Chen CY, Dai CY, Hsiao CF, Lin YJ, Su WC, et al. Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma. Aliment Pharmacol Ther. 2013;37(1):62–73. https://doi​.org/10.1111/apt.12132. [PubMed: 23134470] [CrossRef]
52.
Koeberle D, Dufour JF, Demeter G, Li Q, Ribi K, Samaras P, et al. Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29). Ann Oncol. 2016;27(5):856–61. https://doi​.org/10.1093/annonc/mdw054. [PubMed: 26884590] [CrossRef]
53.
Singal AG, Murphy CC. Hepatocellular carcinoma: a roadmap to reduce incidence and future burden. J Natl Cancer Inst. 2018; https://doi​.org/10.1093/jnci/djy184. [PMC free article: PMC6579741] [PubMed: 30544135] [CrossRef]
54.
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, 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; https://doi​.org/10.1016​/s0140-6736(17)31046-2. [PMC free article: PMC7539326] [PubMed: 28434648] [CrossRef]
55.
Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, 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; https://doi​.org/10.1016​/S1470-2045(18)30351-6. [PubMed: 29875066] [CrossRef]
Copyright 2019, Springer Nature Switzerland AG.
Bookshelf ID: NBK553745PMID: 32078262DOI: 10.1007/978-3-030-21540-8_11
Contents

Views

  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this page (283K)

In this Page

Similar articles in PubMed

See reviews...See all...

Recent Activity