**4. Novel molecularly targeted therapy**

These therapies are targeted against specific molecular signaling pathways involved in HCC carcinogenesis. Several nonrandomized and phase I, II, and III clinical trials have been conducted to examine the role of novel molecularly targeted therapy (monotherapy or combination therapy) for the management of advanced inoperable HCC.

### **4.1. Sorafenib**

Sorafenib is the official first Food and Drug Administration (FDA)-approved monotherapy drug for the management of patients with advanced unresectable HCC, ineligible for surgical resection, liver transplantation, and loco-regional therapies. Several prospective studies have evaluated the efficacy of sorafenib as single-agent (monotherapy) and combination therapy with systemic cytotoxic chemotherapy and loco-regional therapy.

#### *4.1.1. Sorafenib monotherapy*

A total of 7 studies have been conducted on single-agent sorafenib with a sum of 1072 patients.

Table 2 exhibits a summary of major phase I and III studies on single-agent sorafenib for the management of patients with advanced inoperable HCC.

Past, Present, and Future Perspectives on the Systemic Therapy for Advanced Hepatocellular Carcinoma (HCC)... http://dx.doi.org/10.5772/60991 121


The arrival of novel molecularly targeted therapy (specifically sorafenib) is rapidly emerging

That being said, systemic chemotherapy may still be regarded in patients whom their HCC get worse while on sorafenib and whom baseline liver function and performance status are

The chemotherapy-related adverse events of any single-agent or combined regimen should be deliberated cautiously in patients with progressive inoperable HCC, multiple comorbidities, and very short life expectancy. Generally speaking, systemic chemotherapy should be selectively administered to physically and medically fit patients who possess appropriate hepatic functional reserve. Moreover, such administration should be ideally considered only

The choice of systemic chemotherapy should be guided by patients' functional hepatic reserve, physical fitness, prognosis, life expectancy, and most importantly availability of the best

Lastly, the reactivation of viral hepatitis may take place in HCC patients receiving aggressively exhaustive systemic chemotherapeutic regimens. Accordingly, it is crucial and greatly

These therapies are targeted against specific molecular signaling pathways involved in HCC carcinogenesis. Several nonrandomized and phase I, II, and III clinical trials have been conducted to examine the role of novel molecularly targeted therapy (monotherapy or

Sorafenib is the official first Food and Drug Administration (FDA)-approved monotherapy drug for the management of patients with advanced unresectable HCC, ineligible for surgical resection, liver transplantation, and loco-regional therapies. Several prospective studies have evaluated the efficacy of sorafenib as single-agent (monotherapy) and combination therapy

A total of 7 studies have been conducted on single-agent sorafenib with a sum of 1072 patients.

Table 2 exhibits a summary of major phase I and III studies on single-agent sorafenib for the

evidence-based medicine (randomized controlled phase III clinical trials).

recommended to maintain antiviral therapies, whenever deemed necessarily.

combination therapy) for the management of advanced inoperable HCC.

with systemic cytotoxic chemotherapy and loco-regional therapy.

management of patients with advanced inoperable HCC.

as the standard of care in patients with advanced inoperable HCC.

adequate enough to endure it.

120 Recent Advances in Liver Diseases and Surgery

within the context of phase II and III clinical trials.

**4. Novel molecularly targeted therapy**

**4.1. Sorafenib**

*4.1.1. Sorafenib monotherapy*

*n*: sample size; yr: year; CPS: Child-Pugh score; HBV: hepatitis B virus; HCV: hepatitis C virus; DCR: disease control rate; TTP: time to progression; OS: overall survival; HFS: hand-foot syndrome; NR: not reported; mon: months.

**Table 2.** Summary of major phases I-III studies on single-agent sorafenib for the management of patients with advanced inoperable HCC

The numbers of phase I, II, and III studies were 2, 3, and 2, respectively. Overall, the vast majority of patients were elderly (above 50 years), males, CPS-A/CPS-B, and HBV/HCV positive. The DCR ranged from as low as 26% to as high as 82%. TTP ranged from 3 to 5.5 months, whereas OS ranged from 3 to 15.6 months. The most frequent sorafenib-related toxicities were fatigue (range: 0-91%), diarrhea (range: 0-82%), and hand-foot syndrome [HFS] (range: 3-27%).

The two high-quality, large-sized, randomized placebo-controlled phase III trials were the SHARP and Asia-Pacific reports. In both reports, the greater proportions of patients had CPS-A cirrhosis, and these proportions were almost similar (95% and 97%, respectively). However, the occurrence of hepatitis B infection (HBV) was different (19% vs. 71%, respectively). In the SHARP report, in comparison with placebo groups, the sorafenib group achieved higher statistically significant median TTP (5.5 vs. 2.8 months, respectively; *P* < 0.05) and OS (10.7 vs. 7.9 months, respectively; *P* < 0.05). Conversely, in the Asia-Pacific report, in comparison with the placebo groups, the sorafenib group achieved higher statistically significant median TTP (2.8 vs. 1.4 months, respectively; *P* < 0.05) and OS (6.5 vs. 4.2 months, respectively; *P* < 0.05).

The noted differences between TTP and OS between SHARP and Asia-Pacific trials were contemplated, and a question was raised as whether etiology of cirrhosis (HBV vs. HCV) influences the therapeutic response to sorafenib. Subsequently, Bruix et al. conducted subanalyses of SHARP study and showed that the median OS (sorafenib vs. placebo) was highest in patients with HCV cirrhosis (14 vs. 7.4 months; difference: 6.6 months), followed by patients with HBV cirrhosis (9.7 vs. 6.1 months; difference: 3.6 months), and then by patients with underlying alcohol-related liver disease (10.3 vs. 8 months; difference: 2.3 months). The study concluded that HCV (as opposed to HBV) positively influences therapeutic response to sorafenib. Similar conclusions were attained elsewhere in other studies in Korea and Japan.

Exploring prognostic biomarkers of therapeutic responses is necessary. Several molecular (for example, FGF3/FGF4, MET, VEGF/VEGFR, pERK), biochemical (for example, elevated AST) -, and clinical (for example, diarrhea, high blood pressure) [94, 95] factors have been proposed to forecast therapeutic response; however, none has been confirmed and definitely established for employment in clinical practice.

In summary, based on the findings of SHARP and Asia-Pacific phase III trials, sorafenib is the official first Food and Drug Administration (FDA)-approved monotherapy drug for the management of patients with advanced unresectable HCC, ineligible for surgical resection, liver transplantation, and loco-regional therapies [83]. Table 2 exhibits that single-agent sorafenib therapy yields statistically significant, although moderate, clinical improvements in the contexts of DCR, TTP, and OS in males younger than 70 years and have CPS-A cirrhosis. Not much information are existing regarding the effects of single-agent sorafenib therapy in females and in patient populations older than 70 years of age and having advanced CPS-B/ CPS-C cirrhosis. Patients with HCV-related cirrhosis have longer OS and higher DCR rates, whereas patients with HBV-related cirrhosis have shorter OS and lower DCR rates in patients receiving sorafenib. The most frequent sorafenib-related adverse events include fatigue, diarrhea, and HFS.

#### *4.1.2. Sorafenib-based combination therapy*

Several studies have combined sorafenib with loco-regional and systemic therapies in patients with advanced unresectable HCC. Loco-regional therapies mainly include transarterial chemoembolization (TACE), transarterial radioemobolization (TARE), radiation, and others. Systemic therapies mainly include cytotoxic chemotherapeutics, hormonal (somatostatin analog) therapies, and others.

The most frequently studied sorafenib-based combination regimen is sorafenib plus TACE. A recently published meta-analysis in 2014 by Zhang et al. [96] examined six studies published from 2011 to 2013 (*n* = 1254 patients) about the efficacy and safety of sorafenib plus TACE versus TACE alone in patients with intermediate to advanced unresectable HCC. The metaanalysis concluded that the combination therapy of sorafenib plus TACE was associated with higher statistically significant ORR (*P* = 0.021), TTP (*P* = 0.003), and OS (*P* = 0.007); however, greater frequency of grade 3/4 adverse events than in the TACE group.

Prete et al. [97] examined the safety and efficacy of sorafenib plus octreotide in 50 patients with advanced HCC; 16 patients (*n* = 16) were treatment naive (34%), whereas the rest underwent prior local and/or systemic management. Partial response, stable disease, and disease pro‐ gression occurred in 10%, 66%, and 24% of patients, respectively. The median TTP and OS were 7 months and 12 months, respectively. Regimen therapy was generally well endured, and hypertension (4%) and diarrhea (6%) were the most common grade 3/4 drug-related adverse side effects. The study concluded that sorafenib plus octreotide regimen is active and well tolerated and signifies a potential therapeutic choice in such patient population with advanced HCC.

The noted differences between TTP and OS between SHARP and Asia-Pacific trials were contemplated, and a question was raised as whether etiology of cirrhosis (HBV vs. HCV) influences the therapeutic response to sorafenib. Subsequently, Bruix et al. conducted subanalyses of SHARP study and showed that the median OS (sorafenib vs. placebo) was highest in patients with HCV cirrhosis (14 vs. 7.4 months; difference: 6.6 months), followed by patients with HBV cirrhosis (9.7 vs. 6.1 months; difference: 3.6 months), and then by patients with underlying alcohol-related liver disease (10.3 vs. 8 months; difference: 2.3 months). The study concluded that HCV (as opposed to HBV) positively influences therapeutic response to sorafenib. Similar conclusions were attained elsewhere in other studies in Korea and Japan.

Exploring prognostic biomarkers of therapeutic responses is necessary. Several molecular (for example, FGF3/FGF4, MET, VEGF/VEGFR, pERK), biochemical (for example, elevated AST) -, and clinical (for example, diarrhea, high blood pressure) [94, 95] factors have been proposed to forecast therapeutic response; however, none has been confirmed and definitely established

In summary, based on the findings of SHARP and Asia-Pacific phase III trials, sorafenib is the official first Food and Drug Administration (FDA)-approved monotherapy drug for the management of patients with advanced unresectable HCC, ineligible for surgical resection, liver transplantation, and loco-regional therapies [83]. Table 2 exhibits that single-agent sorafenib therapy yields statistically significant, although moderate, clinical improvements in the contexts of DCR, TTP, and OS in males younger than 70 years and have CPS-A cirrhosis. Not much information are existing regarding the effects of single-agent sorafenib therapy in females and in patient populations older than 70 years of age and having advanced CPS-B/ CPS-C cirrhosis. Patients with HCV-related cirrhosis have longer OS and higher DCR rates, whereas patients with HBV-related cirrhosis have shorter OS and lower DCR rates in patients receiving sorafenib. The most frequent sorafenib-related adverse events include fatigue,

Several studies have combined sorafenib with loco-regional and systemic therapies in patients with advanced unresectable HCC. Loco-regional therapies mainly include transarterial chemoembolization (TACE), transarterial radioemobolization (TARE), radiation, and others. Systemic therapies mainly include cytotoxic chemotherapeutics, hormonal (somatostatin

The most frequently studied sorafenib-based combination regimen is sorafenib plus TACE. A recently published meta-analysis in 2014 by Zhang et al. [96] examined six studies published from 2011 to 2013 (*n* = 1254 patients) about the efficacy and safety of sorafenib plus TACE versus TACE alone in patients with intermediate to advanced unresectable HCC. The metaanalysis concluded that the combination therapy of sorafenib plus TACE was associated with higher statistically significant ORR (*P* = 0.021), TTP (*P* = 0.003), and OS (*P* = 0.007); however,

greater frequency of grade 3/4 adverse events than in the TACE group.

for employment in clinical practice.

122 Recent Advances in Liver Diseases and Surgery

*4.1.2. Sorafenib-based combination therapy*

analog) therapies, and others.

diarrhea, and HFS.

Hsu et al. [98] examined the safety and efficacy of sorafenib plus metronomic tegafur/uracil in 53 patients with advanced HCC, all of which (100%) and 72% were CPS-A and Hepatitis B surface antigen positive. Partial response and stable disease occurred in 8% and 49% of patients, respectively. The median TTP and OS were 3.7 months and 7.4 months, respectively. The most common grade 3/4 drug-related adverse side effects included bleeding (8%), HFS (9%), elevated serum lipase enzyme (10%), deranged liver function tests (13%), and generalized weakness (15%).

Petrini et al. [99] investigated the safety and efficacy of sorafenib plus 5-FU in 38 patients with advanced HCC. DCR was 48%, whereas the median TTP and OS were 7.6 months and 12.2 months, respectively. The most common drug-related adverse side effects were HFS (55%) and diarrhea (13%).

Yau et al. [100] investigated the safety and efficacy of sorafenib plus capecitabine plus oxaliplatin in 51 patients with advanced or metastatic HCC (phase II trial). The vast majority of patients had CPS-A (98%) and HBV infection (84%). DCR was 75%, whereas the median TTP and OS were 7.1 months and 10.2 months, respectively. The most common drug-related adverse side effects were HFS (73%) and diarrhea (69%).

Richly et al. [101] investigated the safety and efficacy of sorafenib plus doxorubicin in 47 patients with advanced or metastatic HCC (phase II trial). All patients had CPS-A (100%). DCR was 62%, whereas the median TTP and OS were 6.4 months and 13.7 months, respectively. The most common drug-related adverse side effects were HFS (6%), diarrhea (11%), and generalized weakness (6%).

There was only one randomized, placebo-controlled, phase III trial that examined the efficacy of doxorubicin plus sorafenib (*n* = 47) versus doxorubicin plus placebo (*n* = 49) in patients with advanced unresectable HCC [102]. In contrast to the doxorubicin plus placebo group, the doxorubicin plus sorafenib group achieved higher statistically significant DCR (62% vs. 29%, respectively), TTP (6.4 vs. 2.8 months, respectively), and OS (13.7 vs. 6.5 months, respectively). The frequencies of drug-related adverse events were comparable to those for monotherapies. Despite the survival benefits associated with doxorubicin plus sorafenib, the combination of doxorubicin plus sorafenib is not yet indicated for routine clinical use.

In summary, studies of sorafenib-based combination therapy report better DCR, TTP, and OS benefits when compared to single-agent sorafenib therapy, without increased frequencies of excessive treatment-related toxicities and adverse events. However, the vast majority of the conducted sorafenib-based combination therapy studies were quite small-sized case series reporting preliminary findings, and comprehensive data about patient characteristics and clinical outcomes were not often provided. Thus, it is improper to compare such studies. Moreover, in the only phase III trial by Abou-Alfa et al. [102], it was demonstrated that sorafenib plus doxorubicin regimen is more efficacious than doxorubicin alone but does not automatically deliberate that combination therapy (doxorubicin plus sorafenib) is better than single-agent doxorubicin alone. Further research is needed.

#### *4.1.3. Safety and efficacy of sorafenib in hepatic dysfunction*

The safety of sorafenib in patients with hepatic dysfunction, as determined by Child-Pugh score (CPS), has been explored.

In 2011, Abou-Alfa et al. [103] explored the efficacy and safety of sorafenib in HCC patients with CPS-A (*n* = 98) and CPS-B (*n* = 38). In comparison with CPS-A patients, CPS-B patients achieved lower statistically significant median duration of therapy (1.8 vs. 4 months, respec‐ tively) and OS (3.2 vs. 9.5 months, respectively). Moreover, grade 3/4 adverse events took place in both CPS-A and CPS-B patients and encompassed encephalopathy (3% vs. 13%, respective‐ ly), ascites (3% vs. 5%, respectively), and hyperbilirubinemia (14% vs. 53%, respectively).

Moreover, Pinter et al. [104] examined the efficacy and safety of sorafenib in HCC patients with CPS-A (*n* = 26), CPS-B (*n* = 23), and CPS-C (*n* = 10). Respectively, the median OS was 8.3, 4.3, and 1.5 months. It was concluded that sorafenib is questionable to offer survival advan‐ tages in patients with CPS-C cirrhosis.

Furthermore, Lencioni et al. [105] examined the safety and efficacy of sorafenib in 1586 patients with liver dysfunction in their first interim analysis of the Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib (GIDEON). CPS-B patients experienced more serious adverse events than CPS-A patients (60% vs. 3%, respec‐ tively), higher rates of treatment termination (40% vs. 25%, respectively), and higher frequencies of mortality during treatment up to 1 month from the latest sorafenib dose administration (37% vs. 18%, respectively).

However, Raoul et al. [106] in a subanalysis of SHARP trial concluded that sorafenib was safe and effective in patients with mild to moderate liver dysfunction (equal to or greater than 1.8 times the upper limit of normal) without events of increased hepatic toxicities.

In conclusion, sorafenib has better efficacy and safety profiles in HCC patients with CPS-A than CPS-B and CPS-C. For HCC patients with CPS-B, standard dosing should be initiated and then doses can be adjusted accordingly, whenever deemed necessary. Sorafenib is not recommended for HCC patients with CPS-C. Further research is needed.

#### *4.1.4. Safety and efficacy of sorafenib post liver transplantation*

There are minimal data regarding the safety and efficacy of sorafenib plus immunosuppressive therapies (such as mammalian target of rapamycin [mTOR] or calcineurin inhibitors) in patients with recurrent HCC post orthotopic liver transplantation (OLT).

The largest experienced was reported by Gomez-Martin et al. [107]. Twenty-six patients had recurrent HCC post OLT. Ten and sixteen patients received sorafenib doses at 800 mg and 400 mg daily, respectively, in addition to anti-mTOR as an immunosuppresive therapy post OLT. The overall DCR was 54%, whereas the overall TTP and OS were 6.8 and 19.3 months, respectively. Diarrhea (13%, probably due to sorafenib treatment) and mucositis (8%, probably due to anti-mTOR treatment) were the most frequent adverse events.

However, higher frequencies of therapy-related toxicities and adverse events were document‐ ed in other studies combining sorafenib and anti-mTOR [108-110]. For instance, Staufer et al. [109] reported grade 3/4 adverse events in 92% of patients, 77% of whom terminated sorafenib therapy. However, partial response and stable disease were attained in 1 and 4 patients, respectively.

In summary, the combination of sorafenib plus anti-mTOR is feasible in recurrent HCC patients following OLT. However, therapy should be carefully checked due to the probability of severe adverse events. Dose modification may be needed.

#### **4.2. Antiangiogenic agents**

conducted sorafenib-based combination therapy studies were quite small-sized case series reporting preliminary findings, and comprehensive data about patient characteristics and clinical outcomes were not often provided. Thus, it is improper to compare such studies. Moreover, in the only phase III trial by Abou-Alfa et al. [102], it was demonstrated that sorafenib plus doxorubicin regimen is more efficacious than doxorubicin alone but does not automatically deliberate that combination therapy (doxorubicin plus sorafenib) is better than

The safety of sorafenib in patients with hepatic dysfunction, as determined by Child-Pugh

In 2011, Abou-Alfa et al. [103] explored the efficacy and safety of sorafenib in HCC patients with CPS-A (*n* = 98) and CPS-B (*n* = 38). In comparison with CPS-A patients, CPS-B patients achieved lower statistically significant median duration of therapy (1.8 vs. 4 months, respec‐ tively) and OS (3.2 vs. 9.5 months, respectively). Moreover, grade 3/4 adverse events took place in both CPS-A and CPS-B patients and encompassed encephalopathy (3% vs. 13%, respective‐ ly), ascites (3% vs. 5%, respectively), and hyperbilirubinemia (14% vs. 53%, respectively).

Moreover, Pinter et al. [104] examined the efficacy and safety of sorafenib in HCC patients with CPS-A (*n* = 26), CPS-B (*n* = 23), and CPS-C (*n* = 10). Respectively, the median OS was 8.3, 4.3, and 1.5 months. It was concluded that sorafenib is questionable to offer survival advan‐

Furthermore, Lencioni et al. [105] examined the safety and efficacy of sorafenib in 1586 patients with liver dysfunction in their first interim analysis of the Global Investigation of Therapeutic Decisions in Hepatocellular Carcinoma and of its Treatment with Sorafenib (GIDEON). CPS-B patients experienced more serious adverse events than CPS-A patients (60% vs. 3%, respec‐ tively), higher rates of treatment termination (40% vs. 25%, respectively), and higher frequencies of mortality during treatment up to 1 month from the latest sorafenib dose

However, Raoul et al. [106] in a subanalysis of SHARP trial concluded that sorafenib was safe and effective in patients with mild to moderate liver dysfunction (equal to or greater than 1.8

In conclusion, sorafenib has better efficacy and safety profiles in HCC patients with CPS-A than CPS-B and CPS-C. For HCC patients with CPS-B, standard dosing should be initiated and then doses can be adjusted accordingly, whenever deemed necessary. Sorafenib is not

There are minimal data regarding the safety and efficacy of sorafenib plus immunosuppressive therapies (such as mammalian target of rapamycin [mTOR] or calcineurin inhibitors) in

times the upper limit of normal) without events of increased hepatic toxicities.

recommended for HCC patients with CPS-C. Further research is needed.

patients with recurrent HCC post orthotopic liver transplantation (OLT).

*4.1.4. Safety and efficacy of sorafenib post liver transplantation*

single-agent doxorubicin alone. Further research is needed.

*4.1.3. Safety and efficacy of sorafenib in hepatic dysfunction*

score (CPS), has been explored.

124 Recent Advances in Liver Diseases and Surgery

tages in patients with CPS-C cirrhosis.

administration (37% vs. 18%, respectively).

HCCs are largely vascular neoplasms as increased expressions of micro-vessel concentration and vascular endothelial growth factor (VEGF) have been identified [111-114]. The increased expression of VEGF has been linked to poorer survival outcomes [115-117]. Thus, the inhibition of angiogenesis denotes a highly desired therapeutic target in patients with advanced inop‐ erable HCC. Numerous antiangiogenic drugs have already been introduced in clinical studies in monotherapies and combined therapies. Such drugs include bevacizumab, sunitinib, brivanib, pazopanib, inifanib (ABT-869), cediranib (AZD2171), selumetinib (AZD6244), orantinib (TSU-68), ramucirumab, vatalanib (PTK787/ZK 222584), tivantinib, and others.

In a randomized, placebo-controlled, double-blind, phase III trial (BRISK-PS study) by Llovet et al. [118], a total of 395 HCC patients—who failed sorafenib treatment (during or after therapy) or who were ineligible for sorafenib treatment in the first place—were enrolled in the study. Patients were randomized to receive brivanib (800 mg orally once per day) plus best supportive care (BSC) or placebo plus BSC. In brivanib versus placebo groups, the median OS was 9.4 months vs. 8.2 months (*P* = 0.3307), respectively, whereas TTP was 4.2 months vs. 2.7 months (*P* < 0.001), respectively. Treatment-related study termination occurred in 23% and 7% of brivanib and placebo groups, respectively. Grade 3/4 decreased appetite (10%), hyponatre‐ mia (11%), fatigue (13%), and hypertension (17%) were the most common drug-related harmful frequencies. The study concluded that patients who were previously managed with sorafenib, brivanib therapy did not substantially improve OS.

Tivantinib (ARQ 187) is a selective oral inhibitor of c-Met (tyrosine kinase receptor) with multiple roles in neoplastic cell proliferation, migration, invasion, and angiogenesis [33]. Santoro et al. [119] conducted a randomized placebo-controlled phase II trial and examined the role of tivantinib as a second-line novel molecularly targeted therapy in patients with advanced HCC. Major DCR, TTP and DFS advantages were attained in Met+ patients, with an initial OS inclination favoring tivantinib (HR = 0.47) and no negative effects in Met- patients. For Met+ patients, tivantinib achieved higher DCR (50% vs. 20%) and OS (7.2 months vs. 3.8 weeks) than placebo-treated group [33, 119]. Four drug-related mortalities happened in tivantinib group. Grade 3/4 adverse events in tivantinib group included: neutropenia (14%) and anaemia (11%); none occurred in the placebo groups. The study concluded that tivantinib (compared to placebo) substantially benefited second-line HCC patients, particularly if Met+ patients with well-tolerated drug safety dosing at 240 mg twice daily. There is an ongoing prospective, randomized, double-blind, phase III study of tivantinib in Met-high advanced unresectable HCC patients with one previous administration of systemic therapy [33].

Table 3 exhibits a summary of major phase I and II studies on antiangiogenesis monotherapies in patients with advanced HCC. Among the antiangiogenic drugs, bevacizumab stands out as the most effective single-agent novel molecularly targeted therapy. Objective response and disease stabilization rates can be achieved in 7%-13% and 54%-57%, respectively, whereas PFS and OS durations can achieve durations of 3.5-6.9 months and 12.4 months, respectively. However, the drug-related toxicities of hypertension as well as major bleeding and thromboembolic events are major limiting factors [120-122].


Past, Present, and Future Perspectives on the Systemic Therapy for Advanced Hepatocellular Carcinoma (HCC)... http://dx.doi.org/10.5772/60991 127


*n*: sample size; RR: response rate; DS: disease stabilization; TTP: time to progression; PFS: progression-free survival; OS: overall survival; NR: not reported; mon: months

**Table 3.** Summary of major phases I and II studies on single-agent novel molecularly targeted therapy in advanced HCC patients

In summary, the inhibition of angiogenesis appears to be feasible and promising. The combi‐ nation of antiangiogenic drugs (particularly bevacizumab) and other local/systemic therapies may further enhance survival outcomes in patients with advanced inoperable HCC. Addi‐ tional research is needed and many randomized controlled trials are already in place.

#### **4.3. Epidermal growth factor receptor (EGFR) inhibitors**

For Met+ patients, tivantinib achieved higher DCR (50% vs. 20%) and OS (7.2 months vs. 3.8 weeks) than placebo-treated group [33, 119]. Four drug-related mortalities happened in tivantinib group. Grade 3/4 adverse events in tivantinib group included: neutropenia (14%) and anaemia (11%); none occurred in the placebo groups. The study concluded that tivantinib (compared to placebo) substantially benefited second-line HCC patients, particularly if Met+ patients with well-tolerated drug safety dosing at 240 mg twice daily. There is an ongoing prospective, randomized, double-blind, phase III study of tivantinib in Met-high advanced unresectable HCC patients with one previous administration of systemic therapy [33].

Table 3 exhibits a summary of major phase I and II studies on antiangiogenesis monotherapies in patients with advanced HCC. Among the antiangiogenic drugs, bevacizumab stands out as the most effective single-agent novel molecularly targeted therapy. Objective response and disease stabilization rates can be achieved in 7%-13% and 54%-57%, respectively, whereas PFS and OS durations can achieve durations of 3.5-6.9 months and 12.4 months, respectively. However, the drug-related toxicities of hypertension as well as major bleeding and thrombo-

**therapy** *<sup>n</sup>* **RR**

[122] Schwartz et al. 2006 II Bevacizumab 30 6.7 57 6.4 NR NR [120] Malka et al. 2007 II Bevacizumab 30 12.5 54 NR 3.5 NR [121] Siegel et al. 2008 II Bevacizumab 46 13 NR NR 6.9 12.4 [151] Hoda et al. 2008 II Sunitinib 23 6 35 NR NR NR [152] Zhu et al. 2009 II Sunitinib 34 2.9 47 4.1 3.9 9.8 [153] Faivre et al. 2009 II Sunitinib 37 2.7 35 5.3 3.7 8 [154] Koeberle et al. 2010 II Sunitinib 45 2 40 2.8 2.8 9.3 [155] Finn et al. 2012 II Brivanib 46 4.3 41.3 2.7 NR 9.79 [156] Yau et al. 2009 I Pazopanib 27 7 41 4.6 NR NR

> Inifanib (ABT-869)

Cediranib (AZD2171)

Selumetinib (AZD6244)

Orantinib (TSU-68)

Vatalanib (PTK787)

[161] Zhu et al. 2010 II Ramucirumab 42 NR 50 NR 4.3 NR

[128] Philip et al. 2005 II Erlotinib 38 7.9 59 NR 3.2 13 [129] Thomas et al. 2007 II Erlotinib 40 0 43 NR 3.1 11 [163] O'Dwyer et al. 2006 II Gefitinib 31 3 22.5 NR 2.8 6.5 [164] Ramanathan et al. 2009 II Lapatinib 57 5 35 NR 2.3 6.2

**(%)**

**DS (%)**

**TTP (mon)**

44 8.7 NR 3.7 3.7 9.8

28 0 NR 2.8 NR 5.8

19 0 37.5 2 NR NR

35 8.6 42.8 2.1 NR 13.1

18 0 50 NR NR 7.3

**PFS (mon)**

**OS (mon)**

embolic events are major limiting factors [120-122].

126 Recent Advances in Liver Diseases and Surgery

[157] Toh et al. 2009 II

[158] Alberts et al. 2007 II

[159] O'Neil et al. 2009 II

[160] Kanai et al. 2010 I/II

[162] Koch et al. 2007 I

**Antiangi ogenic agents**

> **Anti-EGFR agents**

**Reference Authors Year Phase Single-agent**

The expression of numerous EGF family members (such as EGF, EGFR, transforming growth factor-alpha [TGF-α], heparin-binding epidermal growth factor, and others) has been con‐ firmed in many HCC cell tissues [123-127]. Thus, disrupting the EGFR signaling pathway denotes a highly desired therapeutic target in patients with advanced inoperable HCC. Subsequently, two major categories of anti-EGFR have been created: EGFR tyrosine kinase inhibitors and monoclonal antibodies against EGFR. Numerous anti-EGFR drugs have already been introduced in clinical studies in monotherapies and combined therapies. Examples of EGFR tyrosine kinase inhibitors include erlotinib, gefitinib, lapatinib, and imatinib. The most commonly used monoclonal antibody against EGFR is cetuximab.

Among the anti-EGFR drugs, erlotinib stands out the most effective single-agent novel molecularly targeted therapy. In two randomized controlled trials [128, 129] examining the role of erlotinib in patients with advanced unresectable HCC, a total of 78 patients were enrolled. Although ORR ranged from 0% to 9%, the average disease stabilization rate reached 51%, whereas average PFR and OS achieved durations of 3 and 12 months, respectively. However, the most frequent drug-related toxicities were skin-related reactions and diarrhea. Apart from the fairly moderate antitumor effects associated with erlotinib, the remaining drugs belonging to EGFR inhibitors have failed to demonstrate any substantial antineoplastic effects as monotherapies in patients with advanced HCC [33].

Table 3 exhibits a summary of major phase I and II studies on single-agent EGFR inhibitors (novel molecularly targeted therapy) in patients with advanced HCC.

In summary, interfering with EGFR signaling pathway appears to be feasible, promising, and an exciting area for future research. The combination of anti-EGFR drugs (particularly erlotinib) and other local/systemic therapies may further enhance survival outcomes in patients with advanced inoperable HCC. Additional research is needed and many randomized controlled trials are already in place.

#### **4.4. Mammalian target of rapamycin (mTOR) inhibitors**

The significance of the mTOR signaling pathway in HCC pathogenesis was explored in a largesized research study involving 314 HCC and 37 noncancerous tissues that utilized a variety of molecular-based laboratory techniques [130]. The major study findings were abnormal mTOR signaling (p-RPS6) in 50% of patients, chromosomal gains in rapamycinin-sensitive companion of mTOR (RICTOR) in 25% of patients, and direct correlation between positive p-RPS6 immunohistochemical staining and HCC recurrence post surgical excision. Thus, disrupting the mTOR signaling pathway designates a highly potential therapeutic target in patients with advanced inoperable HCC. Numerous anti-mTOR drugs have already been introduced in clinical studies in monotherapies and combined therapies. Examples of mTOR inhibitors include everolimus, sirolimus, and temsirolimus.

Among the anti-mTOR drugs, everolimus stands out as the most effective single-agent novel molecularly targeted therapy despite the modest antitumor activities. Dose-limiting adverse events are common and include infection, diarrhea, elevated alanine aminotransferase, elevated total bilirubin, cardiac ischemia, and reactivation of HBV/HCV [131].

Table 3 exhibits a summary of major phase I and II studies on single-agent mTOR inhibitors (novel molecularly targeted therapy) in patients with advanced HCC.

In view of the modest antitumor activities of everolimus, Zhu et al. [132] conducted a multi‐ center, randomized, double-blind, phase III trial (EVOLVE-1) in 546 adult HCC patients who failed sorafenib treatment (during or after therapy) or who were ineligible for sorafenib treatment in the first place. Patients were randomized to everolimus plus best supportive care (BSC) (*n* = 362) and placebo plus BSC (*n* = 184) groups. No statistically significant differences in median TTP and OS were achieved among both treatment groups. However, a statistically significant DCR was achieved in everolimus versus placebo group (56.1% vs. 45.1%, respec‐ tively; *P* = 0.01), and mortality rate was comparable (83.7% vs. 82.1%, respectively). The most frequent grade 3/4 toxicities observed in everolimus versus placebo groups were generalized weakness (7.8% vs. 5.5%, respectively), diminished appetite (6.1% vs. 0.5%, respectively), and anemia (7.8% vs. 3.3%, respectively). No single patient encountered HCV flare-up, however, HBV reactivation was encountered by 29 everolimus and 10 placebo (*n* = 39 patients; overall 7%); all of which were symptom free. The study concluded that administration of everolimus did not improve OS in patients with advanced HCC whose cancer progressed during or after receiving sorafenib or who were intolerant of sorafenib.

#### **4.5. Combination therapy with novel molecularly targeted therapy and systemic chemotherapy**

Table 4 exhibits a summary of phases I and II on combined novel molecularly targeted therapy and systemic chemotherapy in patients with advanced HCC.

Past, Present, and Future Perspectives on the Systemic Therapy for Advanced Hepatocellular Carcinoma (HCC)... http://dx.doi.org/10.5772/60991 129


*n*: sample size; RR: response rate; DS: disease stabilization; TTP: time to progression; PFS: progression-free survival; OS: overall survival; NR: not reported; mon: months

1 Overlap of patient cohorts cannot be excluded from abstracts.

2 Terminated secondary to absence of efficacy.

**Table 4.** Summary of phase II studies on combined novel molecularly targeted therapy and systemic chemotherapy in advanced HCC

Several combination therapy regimens exist, such as bevacizumab based, cetuximab based, and others. Among all, bevacizumab-based regimens appear to have the most effective antitumor effects with ORR achieving 3.7%-25%, disease stabilization 27%-48%, PFS 4.1-7.2 months, and OS 9.5-15.7 months. Future studies comparing sorafenib-based versus bevacizu‐ mab-based combination therapies are needed.

#### **4.6. Conclusion**

erlotinib) and other local/systemic therapies may further enhance survival outcomes in patients with advanced inoperable HCC. Additional research is needed and many randomized

The significance of the mTOR signaling pathway in HCC pathogenesis was explored in a largesized research study involving 314 HCC and 37 noncancerous tissues that utilized a variety of molecular-based laboratory techniques [130]. The major study findings were abnormal mTOR signaling (p-RPS6) in 50% of patients, chromosomal gains in rapamycinin-sensitive companion of mTOR (RICTOR) in 25% of patients, and direct correlation between positive p-RPS6 immunohistochemical staining and HCC recurrence post surgical excision. Thus, disrupting the mTOR signaling pathway designates a highly potential therapeutic target in patients with advanced inoperable HCC. Numerous anti-mTOR drugs have already been introduced in clinical studies in monotherapies and combined therapies. Examples of mTOR inhibitors

Among the anti-mTOR drugs, everolimus stands out as the most effective single-agent novel molecularly targeted therapy despite the modest antitumor activities. Dose-limiting adverse events are common and include infection, diarrhea, elevated alanine aminotransferase,

Table 3 exhibits a summary of major phase I and II studies on single-agent mTOR inhibitors

In view of the modest antitumor activities of everolimus, Zhu et al. [132] conducted a multi‐ center, randomized, double-blind, phase III trial (EVOLVE-1) in 546 adult HCC patients who failed sorafenib treatment (during or after therapy) or who were ineligible for sorafenib treatment in the first place. Patients were randomized to everolimus plus best supportive care (BSC) (*n* = 362) and placebo plus BSC (*n* = 184) groups. No statistically significant differences in median TTP and OS were achieved among both treatment groups. However, a statistically significant DCR was achieved in everolimus versus placebo group (56.1% vs. 45.1%, respec‐ tively; *P* = 0.01), and mortality rate was comparable (83.7% vs. 82.1%, respectively). The most frequent grade 3/4 toxicities observed in everolimus versus placebo groups were generalized weakness (7.8% vs. 5.5%, respectively), diminished appetite (6.1% vs. 0.5%, respectively), and anemia (7.8% vs. 3.3%, respectively). No single patient encountered HCV flare-up, however, HBV reactivation was encountered by 29 everolimus and 10 placebo (*n* = 39 patients; overall 7%); all of which were symptom free. The study concluded that administration of everolimus did not improve OS in patients with advanced HCC whose cancer progressed during or after

elevated total bilirubin, cardiac ischemia, and reactivation of HBV/HCV [131].

**4.5. Combination therapy with novel molecularly targeted therapy and systemic**

Table 4 exhibits a summary of phases I and II on combined novel molecularly targeted therapy

(novel molecularly targeted therapy) in patients with advanced HCC.

receiving sorafenib or who were intolerant of sorafenib.

and systemic chemotherapy in patients with advanced HCC.

**chemotherapy**

controlled trials are already in place.

128 Recent Advances in Liver Diseases and Surgery

**4.4. Mammalian target of rapamycin (mTOR) inhibitors**

include everolimus, sirolimus, and temsirolimus.

Sorafenib remains the first-line standard of care management in patients with advanced unresectable HCC. Multimodal therapy with sorafenib and other local/systemic therapy is an exciting area for future exploration. Absolute advantages of combining novel molecularly targeted therapy (sorafenib or bevacizumab) and cytotoxic chemotherapy is not yet surely defined. Much more research is needed about efficacy of existing combination systemic therapy (cytotoxic chemotherapy plus novel molecularly targeted therapy) versus sorafenib alone (the first-line therapy so far) for the management of patients with advanced unresectable HCC. Such studies should be addressed through large-sized randomized controlled phase II and III trials; some of which are already ongoing.

Several genetic and epigenetics take place during hepatocarcinogenesis. These signaling pathways include the Wnt-b-catenin pathway, the hepatocyte growth factor/c-Met pathway, IGF and IGF-R pathways, and PI3 K/Akt/mTOR pathway. Several drugs targeting these significant pathways are currently undergoing early-stage assessment in patients with HCC [33, 133].
