Clinical trials of antiangiogenic therapy for hepatocellular carcinoma

Angiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of antiangiogenic agents in hepatocellular carcinoma. A systematic search of PubMed was performed to identify clinical trials of specific antiangiogenic agents in hepatocellular carcinoma treatment, particularly phase III trials involving treatment guidelines for advanced hepatocellular carcinoma. Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma. Two large-scale, randomized phase III trials using sorafenib involving patients with unresectable HCC showed a significant survival benefit compared with placebo control groups. However, subsequent phase III trials of antiangiogenic agents in hepatocellular carcinoma have failed to improve survival compared with standard treatment protocols using sorafenib. The efficacy of antiangiogenic agents in combination with other drugs, transarterial chemoembolization, and surgical resection is currently being investigated. Future research is expected to optimize antiangiogenic therapies in combination with standard treatment with sorafenib.     

Safety and anti-tumor activity of sorafenib (Nexavar®) in combination with other anti-cancer agents: a review of clinical trials

Purpose

Sorafenib (Nexavar^®) is an oral multi-kinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. Sorafenib has demonstrated preclinical and clinical activity against several tumor types, as a monotherapy and in combination with other anti-cancer agents.

Methods

This review summarizes the safety, pharmacokinetics, and anti-tumor activity of sorafenib combined with other targeted agents or cytotoxics from a series of Phase I/II trials in approximately 600 patients with advanced solid tumors.

Results

Sorafenib in combination with other agents was generally well tolerated, and most adverse events were mild to moderate in severity. Frequent drug-related toxicities were dermatologic, gastrointestinal, or constitutional. Most trials supported sorafenib 400 mg bid as the recommended dose for combination. Sorafenib generally had little effect on the pharmacokinetics of coadministered agents and vice versa. Preliminary anti-tumor activity was observed; overall disease control rates (partial response plus stable disease) ranged from 33 to 92%. Particularly promising activity was observed in patients with melanoma, hepatocellular carcinoma, and non-small-cell lung cancer receiving sorafenib plus paclitaxel/carboplatin, doxorubicin, and gefitinib, respectively.

Conclusions

Sorafenib demonstrated a good safety profile and encouraging anti-tumor effects when coadministered with other agents in patients with advanced solid tumors.     

Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors

Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer.     

Off-label use of cetuximab plus sorafenib and panitumumab plus regorafenib to personalize therapy for a patient with V600E BRAF-mutant metastatic colon cancer

Sorafenib, the first agent developed to target BRAF mutant melanoma, is a multi-kinase inhibitor that was approved by the FDA for therapy of kidney and subsequently liver cancer, and is currently in clinical trials for thyroid, lung and brain cancer. Colorectal cancer with V600E BRAF mutation has shown relative resistance to standard chemotherapy regimens, as well as lack of efficacy to vemurafenib in clinical trials. New treatments are needed for BRAF-mutant colorectal cancer. We report a case of a patient with BRAF-mutant metastatic colon cancer whose disease had progressed on FOLFOX plus bevacizumab and subsequent FOLFIRI plus cetuximab. Based on preclinical data published in Nature in 2012 suggesting that successful therapeutic targeting of BRAF in colorectal cancer may require concomitant targeting of the EGFR, we offered this patient without other attractive options the combination of sorafenib plus cetuximab, in off-label use with informed consent. Sorafenib and cetuximab therapy led to a mixed radiographic response with some areas showing dramatic improvement and other areas showing stable disease over a 7-month period which is a notably long period of progression-free survival for V600E BRAF mutated colon cancer. The cetuximab plus sorafenib therapy was very well-tolerated by the patient who remained on it long enough until another therapy option, regorafenib, was approved in September 2012. The patient was offered single agent regorafenib at the time of progression. At the time of progression on single agent regorafenib, panitumumab was combined with regorafenib and this was also well-tolerated and appeared to slow disease progression. Further study of these approaches in the clinic as personalized treatment of BRAF-mutant advanced colorectal cancer is warranted.     

Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer

Despite the optimization of chemotherapy regimens, treatment outcomes for advanced non-small cell lung cancer (NSCLC) are still considered to be disappointing. Thus, clinical research of new treatment strategies is warranted. Several targeted agents have been introduced into clinical trials in NSCLC, but to date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. One of the main reasons for the failure of several clinical trials of targeted therapy in lung cancer is that there is multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events; blocking only one of these pathways, as most first-generation targeted agents do, allows others to act as salvage or escape mechanisms for cancer cells. Sorafenib and sunitinib are two oral multitargeted receptor tyrosine kinase inhibitors. Sorafenib is a multikinase inhibitor that inhibits the kinase activity of both C-RAF and B-RAF and targets the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and stem cell factor receptor [KIT]). Sunitinib is a multitargeted inhibitor of PDGFR, KIT, fms-like tyrosine kinase 3, and VEGFR. The kinases targeted and inhibited by sorafenib and sunitinib directly and indirectly regulate tumor growth, survival, and angiogenesis, and this might be expected to result in broad antitumor efficacy. Sorafenib and sunitinib have been approved by the U.S. Food and Drug Administration for the treatment of metastatic renal cell carcinoma; sunitinib has also been approved for the treatment of gastrointestinal stromal tumors. Their mechanism of action, preclinical data, and phase II studies suggest efficacy in the treatment of advanced NSCLC.     

Antiangiogenic agents in the management of non-small cell lung cancer: Where do we stand now and where are we headed?

Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, BIBF 1120, sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751, and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.     

Sorafenib in patients with refractory or recurrent multiple myeloma

Sorafenib is a small molecular inhibitor of several tyrosine protein kinases, including vascular endothelial growth factor receptor, platelet‐derived growth factor receptor and rapidly accelerated fibrosarcoma kinases, targeting signal transduction and angiogenic pathways. It is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. The objectives of this prospective phase II trial were to assess the activity and tolerability of sorafenib in patients with recurrent or refractory myeloma. In total, 11 patients were enrolled. Patients received 2 × 200 mg of sorafenib orally twice daily until completing 13 full cycles or disease progression. Of the side effects, 8.8% grade 3 and 1.1% grade 4 occurred. Sorafenib treatment was effective in two patients who achieved a partial response and a continuous stable disease with duration of 24.4 months and 6.9 month, respectively. Further clinical investigations are recommended to investigate sorafenib single agent activity in myeloma subgroups with ras‐/BRAF‐/vascular endothelial growth factor receptor pathway activation and combination therapy approaches. Copyright © 2013 John Wiley & Sons, Ltd.     

Early development of sunitinib in hepatocellular carcinoma

Sunitinib malate is an oral, multitargeted receptor tyrosine kinase inhibitor of VEGF receptors 1, 2 and 3; PDGF receptors α and β, and other receptor tyrosine kinases implicated in tumor growth, angiogenesis and metastasis. Hepatocellular carcinoma (HCC) is a highly vascular tumor that overexpresses several angiogenic factors; VEGF and PDGF signaling pathways play a key role in HCC. Until recently, treatment options for advanced HCC were limited and conventional therapies have met with poor response rates. Sorafenib provided proof-of-concept for molecularly targeted therapy in advanced HCC and has recently been approved for treatment. However, not all patients can tolerate sorafenib and patients may experience tumor progression; therefore, additional treatment options are warranted. Sunitinib has shown early evidence of anti-tumor activity in Phase II trials in US, European and Asian patients with locally advanced, unresectable and metastatic HCC. A Phase III trial of sunitinib in HCC is ongoing.     

Selected combination therapy with sorafenib: a review of clinical data and perspectives in advanced solid tumors

The development of targeted therapies has provided new options for the management of patients with advanced solid tumors. There has been particular interest in agents that target the mitogen-activated protein kinase pathway, which controls tumor growth and survival and promotes angiogenesis. Sorafenib is an oral multikinase inhibitor that has been proven effective as a single-agent therapy in renal cell carcinoma, and there is a strong rationale for investigating its use in combination with other agents. In particular, targeting multiple Raf isoforms with sorafenib may help to overcome resistance to other agents, while the ability of sorafenib to induce apoptosis may increase the cytotoxicity of chemotherapeutic agents. Based on positive results in preclinical studies, further investigation in phase I and II studies has shown potential antitumor activity when sorafenib is combined with cytotoxic agents in different solid tumors, including hepatocellular carcinoma and melanoma. Promising results have been reported in phase I and II studies of sorafenib combined with paclitaxel and carboplatin, with oxaliplatin in gastric and colorectal cancer, with docetaxel in breast cancer, with gemcitabine in ovarian cancer, and with capecitabine in different solid tumors. Phase II and III studies are currently investigating the use of sorafenib in combination with different agents in a variety of solid tumors. The primary objective of this review is to summarize the early clinical studies of sorafenib with cytotoxic agents and discuss future perspectives of these combinations in different tumor types.     

Enhancing the clinical activity of sorafenib through dose escalation: rationale and current experience

Sorafenib is an oral multitargeted tyrosine and serine/threonine kinase inhibitor approved for the treatment of advanced renal cell and hepatocellular carcinoma. An understanding of its dose-toxicity relationship has paved the way for trials seeking to enhance its clinical activity through the exploration of alternative dosing strategies. In this article, we review the dose-toxicity relationship of sorafenib observed during its phase I and early phase II testing, explore its toxicity profile at the recommended dose and schedule, discuss the evidence for dose escalation to higher levels, and examine the preliminary evidence for clinical activity of this strategy. Owing to a temporal relationship between toxicity and dose, it may be possible in select patients to escalate sorafenib to doses beyond those currently employed. However, because of the potential for increased toxicity, sorafenib dose escalation should currently be performed only in the context of a clinical trial.     

肿瘤靶向治疗新探:多靶点Raf激酶抑制剂

随着对肿瘤分子机制的加深理解，对肿瘤分子靶向治疗的研究已获重大进展。蛋白激酶抑制剂是新近研发的靶向治疗药物之一，通过阻碍细胞内分子传导通路，影响肿瘤细胞的存活、增殖以及疾病进展。在Raf／MEK／ERK信号传导通路中，Raf激酶发挥着至关重要的作用。尽管在正常组织中Raf激酶的功能尚未明朗，但现有的基础及临床研究结果均显示，Raf基因的上调及其蛋白的过度表达存在于多种实体肿瘤之中，包括肾细胞癌、肝细胞癌、黑色素瘤以及非小细胞肺癌等。索拉非尼是全球首个口服的Raf激酶抑制剂。此外，作为一个多靶点药物，索拉非尼同时具有针对包括VEGFR与PDGFR的广泛酪氨酸激酶受体抑制功能。目前美国FDA已经批准索拉非尼用于治疗转移性肾癌。另外，该药物在针对黑色素瘤、肝癌、胰腺癌以及非小细胞肺癌的临床研究中也已经显示出一定的疗效。本综述将简要说明Raf激酶在正常与肿瘤细胞中的功能以及在不同肿瘤中的作用机制，并重点介绍索拉非尼的临床应用及研究。     

Sorafenib in der Therapie des fortgeschrittenen Nierenzellkarzinoms

Sorafenib is a novel, orally active multikinase inhibitor targeting various serine/threonine- and receptor tyrosinkinases. Sorafenib reduces in vitro and in vivo tumor cell proliferation and tumor angiogenesis. Its efficacy and safety have been demonstrated in two placebo controlled trials. The phase II randomized discontinuation trial (RTD) evaluated the effects of sorafenib on tumor growth in patients with renal cell carcinoma (RCC). Of 202 patients treated during the run-in period, 73 showed a tumor shrinkage of ≥25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n=32) or placebo (22%). At 24 weeks, 50% of the sorafenib-treated patients were progression free vs 18% of the patients with placebo. Median progression-free survival (PFS) from randomization was significantly longer with sorafenib than placebo. Median overall PFS was 29 weeks for the entire RCC population. Sorafenib was readministered in 28 patients whose disease progressed on placebo; these patients continued on sorafenib until further progression for a median of 24 weeks. A phase III randomized double-blind, placebo-controlled trial of sorafenib was performed in patients with advanced RCC. A total of 903 patients were randomized with 216 placebo patients crossing over to sorafenib. The trial demonstrated an estimated 39% improvement in survival for patients receiving sorafenib versus placebo. These data support an independently reviewed doubling of PFS to 24 weeks in RCC patients receiving sorafenib compared with placebo. At the time of analysis, there were 367 deaths. The median OS was 19.3 months for sorafenib versus 15.9 months for placebo. Although this did not attain the level of significance specified for the interim analysis, a continued favorable trend in survival benefit was documented. For the crossover data, the OS was 19.3 months for sorafenib versus 14.3 months for placebo. Final results await more complete data. Common adverse events were qualitatively similar to those found in the phase II trial.     

Sorafenib: delivering a targeted drug to the right targets

Approved for the treatment of advanced renal cell carcinoma by the US FDA and other regulatory agencies, sorafenib is an agent with multiple targets that may also prove beneficial in other malignancies. Phase III trials are underway in melanoma, hepatocellular carcinoma and non-small-cell lung cancer. Scrutiny of the Phase II data and correlative studies conducted in that context suggests that inhibition of angiogenesis and signaling in tumor cells may play a part in the clinical efficacy of sorafenib. Although the vascular endothelial growth factor receptor inhibitors are the most populated class of targeted agents in cancer clinical trials, sorafenib may prove to have unique properties that distinguish it. A detailed discussion of the clinical trials in renal cell carcinoma, melanoma and hepatocellular carcinoma highlights what is known and what has yet to be understood about this agent.     

Sorafenib: delivering a targeted drug to the right targets

Approved for the treatment of advanced renal cell carcinoma by the US FDA and other regulatory agencies, sorafenib is an agent with multiple targets that may also prove beneficial in other malignancies. Phase III trials are underway in melanoma, hepatocellular carcinoma and non-small-cell lung cancer. Scrutiny of the Phase II data and correlative studies conducted in that context suggests that inhibition of angiogenesis and signaling in tumor cells may play a part in the clinical efficacy of sorafenib. Although the vascular endothelial growth factor receptor inhibitors are the most populated class of targeted agents in cancer clinical trials, sorafenib may prove to have unique properties that distinguish it. A detailed discussion of the clinical trials in renal cell carcinoma, melanoma and hepatocellular carcinoma highlights what is known and what has yet to be understood about this agent.     

Nivolumab for the treatment of hepatocellular carcinoma

Introduction: T-cell checkpoint inhibition as a cancer treatment approach has been the main breakthrough in cancer treatment during the last years. Since the approval of the first commercial CTLA-4 antibody ipilimumab in 2011 for the treatment of melanoma, research and drug development in this field has accelerated massively. In 2014, the US Food and Drug Administration (FDA) approved the first PD-1 targeting agent, namely pembrolizumab, shortly followed by nivolumab.

Areas covered: Nivolumab is a fully human immunoglobulin G4 anti-PD-1 monoclonal antibody which is approved for multiple advanced malignancies, including melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin’s lymphoma, squamous head and neck cancer, and urothelial carcinoma. In September 2017, nivolumab was approved by the FDA for liver cancer as a second line treatment after failure of sorafenib based on the data of the multi-cohort phase 1/2 trial CheckMate-040. This article reviews the concept of immunotherapy in liver cancer with focus on nivolumab.

Expert commentary: Immunotherapy in hepatocellular carcinoma is safe and is a new treatment option for patients with advanced stage disease besides sorafenib and regorafenib in the US. Randomized phase III trials of nivolumab, pembrolizumab, atezolizumab, durvalumab and tislelizumab as mono- or combination-therapy are ongoing.     

Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome?

In this analysis of the safety and efficacy of BAY 43-9006 (sorafenib) -- a novel, oral multi-kinase inhibitor with effects on tumour and its vasculature -- pooled data were obtained from four phase I dose-escalation trials. Time to progression (TTP) was compared in patients with/without grade 2 skin toxicity/diarrhoea. Grade 3 hand-foot skin reactions (HFS; 8%) and diarrhoea (6%) were common. At the recommended 400mg bid dose for phase II/III trials (RDP), 15% of patients experienced grade 2/3 HFS, and 24% experienced grade 2/3 diarrhoea. Sorafenib induced stable disease for 6 months in 12% of patients (6% stabilized for 1 year). Patients receiving sorafenib doses at or close to the RDP, who experienced skin toxicity/diarrhoea, had a significantly increased TTP compared with patients without such toxicity (P < 0.05). Sorafenib was well tolerated at the RDP, and induced sustained disease stabilization, particularly in patients with skin toxicity/diarrhoea.     

Drug Treatment for Advanced Hepatocellular Carcinoma: First-Line and Beyond

Hepatocellular carcinoma (HCC) has high mortality. The option of systemic therapy has increased significantly over the past five years. Sorafenib was the first multikinase inhibitor, introduced in 2007, as a treatment option for HCC, and it was the only effective systemic treatment for more than ten years. It was not until 2017 that several breakthroughs were made in the development of systemic strategies. Lenvatinib, another multikinase inhibitor, stood out successfully after sorafenib, and has been applied to clinical use in the first-line setting. Other multikinase inhibitors such as regorafenib, ramucirumab and cabozantinib, were approved in quick succession as second-line therapies. Concurrently, immune checkpoint inhibitors (ICIs) have readily become established treatments for many solid tumors, including HCC. The most studied ICIs to date, target programmed cell death-1 (PD-1), its ligand PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). These ICIs have demonstrated efficacy in treating advanced HCC. More recently, combination of bevacizumab and atezolizumab (ICI targeting PD-L1) was approved as the gold-standard first-line therapy. Combination of ICIs with nivolumab and ipilimumab was also approved in the second-line setting for those who failed sorafenib. At the moment, numerous clinical trials in advanced HCC are underway, which will bring continuous change to the management, and increase the survival, for patients with advanced HCC. Our review article: (1) summarizes United States Food and Drug Administration (US FDA) approved systemic therapies in advanced HCC, (2) reports the evidence of currently approved treatments, (3) discusses potential drugs/drug combinations being currently tested in phase III clinical trials, and (4) proposes possible future directions in drug development for advanced HCC.     

Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway

Improvements in our understanding of the molecular basis of cancer have led to the clinical development of protein kinase inhibitors, which target pivotal molecules involved in intracellular signaling pathways implicated in tumorigenesis and progression. These novel targeted agents have demonstrated activity against a wide range of solid tumors, are generally better tolerated than standard chemotherapeutics, and may revolutionize the management of advanced refractory cancer. The ubiquitous Raf serine/threonine kinases are pivotal molecules within the Raf/mitogen extracellular kinase (MEK)/extracellular signal-related kinase (ERK) signaling pathway, which regulates cellular proliferation and survival. Raf kinase isoforms (wild-type Raf-1 or the b-raf V600E oncogene) are overactivated in a variety of solid tumor types, including renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), melanoma, and papillary thyroid carcinoma. In this review, the role of Raf in normal cells and in cancer is discussed, and an overview is given of Raf inhibitors currently in development, focusing on sorafenib tosylate (BAY 43-9006 or sorafenib). Sorafenib is the first oral multi-kinase inhibitor to be developed that targets Raf kinases (Raf-1, wild-type B-Raf, and b-raf V600E), in addition to receptor tyrosine kinases associated with angiogenesis (vascular endothelial growth factor receptor [VEGFR]-2/-3, platelet-derived growth factor receptor [PDGFR]-beta) or tumor progression (Flt-3, c-kit). Preclinical and clinical sorafenib data that led to its recent approval for the treatment of advanced RCC are summarized, along with current thinking on sorafenib's mechanism of effect on the tumor and tumor vasculature in melanoma and RCC.     

索拉菲尼治疗肝癌常见不良反应及处理的研究进展

索拉菲尼是一种口服多激酶抑制剂。通过作用于Raf激酶直接抑制肿瘤细胞增殖,还可作用于血管内皮生长因子受体1,2,3（VEGFR-1, -2, -3）,以及血小板源生长因子受体-β（PDGFR-β）、受体酪氨酸激酶、抑制肿瘤新生血管生成。索拉菲尼通过抑制肿瘤细胞增殖和抗血管生成的双重作用,从而达到抗肿瘤的目的。已被多个国家批准作为首个系统治疗肝细胞肝癌的分子靶向药物。其常见不良反应包括皮肤反应、恶心、腹泻、体质量减轻、高血压等,影响了患者的长期使用依从性,进而影响治疗效果。正确地认识和管理索拉非尼的不良反应则有助于发挥索拉非尼的治疗作用,提高临床效果。本文从索拉菲尼靶向治疗的常见不良反应、发生机制及处理方法等方面进行综述。      

Current status of molecularly targeted therapy for hepatocellular carcinoma: clinical practice

In recent years, molecular-targeted agents have been used clinically to treat various malignant tumors. In May 2009, sorafenib (Nexavar^®) was approved in Japan for “unresectable hepatocellular carcinoma (HCC)”, and was the first molecular-targeted agent for use in liver cancer. To date, sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase III randomized controlled trials, and it has now been approved worldwide. Phase III clinical trials are now underway to compare other molecular-targeted agents with sorafenib as first-line treatment agents, and to evaluate other multi-kinase inhibitors of the vascular endothelial growth factor and platelet-derived growth factor receptors, as well as drugs targeting the epidermal growth factor receptor, insulin-like growth factor receptor, and mammalian target of rapamycin, in addition to other molecules targeting other components of the signal transduction pathways. This review outlines the main pathways involved in the development and progression of HCC and the agents that target these pathways.