Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P38 pptx

Chapter 22 Targeted Therapies for Hepatocellular Carcinoma Jonas W. Feilchenfeldt, Eileen M. O’Reilly, Costantine Albany, and Ghassan K. Abou-Alfa Keywords HCC targeted therapies · Sorafenib · Bevacizumab · Sunitinib · Tyrosine kinase inhibitors (TKIs) · Erlotinib · HCC etiology The liver’s role in xenobiotic metabolism, i.e., the modification of drugs and toxic foreign compounds, has long served as a putative explanation for inherent drug resistance of hepatocellular carcinoma (HCC). Therefore, it does not come as a surprise that the initial discovery of the multiple-drug resistance gene (MDR) was in liver tissue [1], and hepatocyte cell lines are a natural reservoir for the study of drug resistance. Accordingly, liver cancer should be a disease where a therapeutic strategy based on an understanding of disease biology would prevail over a cytotoxic strategy where compounds are neutralized before reaching their target. Indeed while cytotoxic agents have failed to show a clinically meaningful impact [2] several clinical trials using targeted treatments such as tyrosine kinase inhibitors have demonstrated that in HCC overall survival may be favorably influenced [3]. In addition to the multikinase inhibitor, sorafenib, which has demonstrated an improvement in survival over placebo [4], over the past decade several different classes of targeted treatments have been clinically tested and can be sub-classified as tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, erlotinib) or antibodies targeted to growth factors (e.g., bevacizumab) and their receptors (e.g., cetuximab) (Fig. 22.1). As the historically evolved clinical expertise in the care for patients with liver disease traditionally has been in the domain of gastroenterologists, education regarding new therapies in HCC is critical to the wider range of medical disciplines currently involved in delivering care to these patients. The significance of this is illustrated by a thought-provoking study lead by Chen et al. from Taiwan, an area with high prevalence of HCC due to hepatitis B [5]. Comparing overall survival of 397 patients with HCC (all stages included) managed by high-volume physicians (70% patients G.K. Abou-Alfa (B) Department of Gastrointestinal Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 355 K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma, DOI 10.1007/978-1-60327-522-4_22, C  Springer Science+Business Media, LLC 2011 356 J.W. Feilchenfeldt et al. Fig. 22.1 Therapeutic targets and their corresponding pathways in HCC. Description of major signaling pathways in hepatocellular carcinoma and associated targets of drugs used in clinical practice respectively ongoing experimental studies. Growth factors: HGF, hepatocyte growth factor; EGF, epidermal growth factor; SCF, stem cell factor; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor; IGF-I, insulin-like growth factor-I. Receptors:IGF- I, insulin-like growth factor receptor 1 and 2; c-met, hepatocyte growth factor receptor. Targets: PI3 kinase, phosphatidylinositol 3-kinase; PDK1, 3-phosphoinositide-dependent protein kinase 1. Experimental Compounds: IMC-A12, insulin growth factor receptor inhibitor; AZD-6244, MEK1/2 inhibitor with liver disease) versus low-volume physicians (less than 30%), a notable survival difference of 34 months versus 6 months was found (hazard ratio [HR] for survival, 1.94; 95% CI, 1.31–2.87; p < 0.001). Despite proven clinical benefit of targeted treatment options, monitoring response to treatment and optimal patient selection based on prediction of treatment efficacy are unresolved questions and areas of ongoing research. This is in part a consequence of an incomplete understanding of the mechanism of action of the drugs, and also the difficulty in formally studying new imaging modalities, as well as validation of such modalities in a multicenter setting. Unexpectedly, the advances generated by targeted agents have created a renewed interest in standard chemother- apeutic agents which may ultimately reveal their potency in combination with biological agents [6]. The impact of liver function and the etiology of liver failure, whose etiologic spectrum comprises entities as diverse as viral, toxic, and metabolic origins, has been extensively studied as part of the development of sorafenib and related targeted agents. Given the multitude of clinically active compounds being assessed in phase II trials, further refinement of therapeutic monitoring, impacts 22 Targeted Therapies for Hepatocellular Carcinoma 357 on liver function, and etiology-driven clinical trials will be necessary to define the optimal clinical setting for such new agents. Antiangiogenic Drugs Sorafenib is a polyvalent molecule which has been shown in HCC cell lines to inhibit the serine–threonine kinase Raf-1 and several receptor tyrosine kinases such as vascular endothelial growth factor receptor (VEGFR2), platelet-derived growth factor receptor (PDGFR), FLT3, Ret, and c-Kit [7] (Fig. 22.1). Several of these pathways, e.g., ras-raf and VEGF, have been implicated in HCC carcinogenesis. Moreover, reduced angiogenesis along with increased apoptosis was observed in a human HCC xenograft tumor model when treated with sorafenib [8]. Following the initial observation of a partial response in a metastatic HCC patient in a phase I trial [9], a phase I I study in HCC was undertaken to better assess efficacy, toxicity, and pharmacokinetics of sorafenib [10]. One hundred and thirty-seven patients were treated with sorafenib 400 mg twice daily. Seventy-two percent of patients had a Child-Pugh score of A and 28% a Child-Pugh score of B. The median time to progression was 4.2 months and the median overall survival was 9.2 months. The main drug-related grades 3 and 4 adverse effects were diarrhea (8%), hand- foot skin reaction (5.1%), and fatigue (9.5%). As clinical benefit does not routinely correlate with volume-based tumor response criteria such as WHO criteria in HCC, tumor necrosis was evaluated and quantified based on serial contrast-enhanced computed tomography (CT). In an exploratory analysis this mode of tumor assessment revealed that tumor necrosis may represent a marker of treatment efficacy despite a concomitant increase in tumor volume and potentially predict clinical benefit from treatment [10]. The current standard of care of sorafenib as systemic therapy for metastatic HCC is based on two phase III studies: the SHARP trial [4] and the Asia-Pacific trial [11]. The SHARP trial is an international, multicenter, phase III, double-blind trial randomly assigning 602 patients to either sorafenib 400 mg twice daily or placebo, with a primary endpoint of overall survival. Patients were recruited from the Western hemisphere, with main etiologies for HCC being hepatitis C (26%), hepatitis B (19%), and alcohol (26%). Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% CI, 0.55–0.87; p < 0.001). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (p < 0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response and with no complete response in either study arm. Grades 3 and 4 side effects included diarrhea (8%) and hand-foot syndrome (8%). Bleeding was a rare event. The Asia-Pacific trial is a multicenter phase III, double-blind trial randomly assigning 226 patients in a 2:1 ratio to either sorafenib 400 mg twice daily (n = 150) versus placebo (n = 76) [11]. As the name implies, patients were recruited mainly in Asia, where the highest prevalent etiology is hepatitis B for HCC. Median overall 358 J.W. Feilchenfeldt et al. survival was 6.5 months (95% CI, 5.56–7.56) in patients treated with sorafenib compared with 4.2 months (3.75–5.46) in those who received placebo (hazard ratio [HR] 0.68; 95% CI, 0.50–0.93; p = 0.014). Median time to progression was 2.8 months (2.63–3.58) in the sorafenib group compared with 1.4 months (1.35–1.55) in the placebo group (HR 0.57 [0.42–0.79]; p = 0.0005). The commonest grades 3 and 4 side effects were hand-foot syndrome, diarrhea, and fatigue. Despite the similar hazard ratios of survival improvement, the disproportionate magnitude of survival improvement between the SHARP and the Asia-Pacific studies is notewor- thy and will be discussed later in view of the implication for sorafenib and other agents regarding the underlying cause of the HCC. The improvement in overall survival, the manageable toxicity, and the targeted action of sorafenib motivated further studies to improve its clinical efficacy. A recently completed randomized phase II trial assessing sorafenib in combination with doxorubicin in HCC demonstrated significant improvement in time to progression, progression-free survival, and overall survival in favor of the combination therapy [6]. This study is discussed in detail in the combination therapy chapter. Vascular endothelial growth factor (VEGF) plays a prognostic [12, 13] and pos- sibly a pathogenetic role in HCC. As a single agent, bevacizumab, an anti-VEGF A antibody (Fig. 22.1), has previously demonstrated significant clinical activity in metastatic renal cancer [14]. Based on the aforementioned biological rationale, 30 patients with advanced HCC were treated with bevacizumab initially at a dosage of 5 mg/kg. As 12 patients progressed with 16 weeks of treatment, the dose was sub- sequently increased to 10 mg/kg. Main reported adverse events were bleeding from varices, transient ischemic attack, hemorrhagic ascites, and proteinuria. Among the 24 patients evaluable for efficacy, 3 patients had a partial response and 13 had stable disease [15]. In a similar study, 46 patients with unresectable HCC were treated with bevacizumab at a dosage of 5–10 mg/kg once every 2 weeks [16]. One complete response and five partial responses were observed; the median overall survival was 12.4 months. Grades 3 and 4 adverse events included hypertension (15%), thrombo- sis (6%), and hemorrhage (11%). The improved overall survival compares favorably with a standard of care, sorafenib. Given EGFR-dependent regulation of VEGF and conversely the existence of VEGF-mediated resistance to EGFR-inhibition [17], the anti-VEGFR, bevacizumab, has been explored in combination with the tyrosine kinase inhibitor, erlotinib, in HCC [18] and this study will be reviewed in the next chapter. Sunitinib is a multikinase i nhibitor targeting VEGF and PDGF receptor pathways [19] both of which play a role in HCC (Fig. 22.1). A phase II study recruited 37 patients with unresectable HCC from Europe and Asia. Sunitinib was dosed at 50 mg daily for 4 weeks followed by a 2 weeks break cycle [20]. Median overall survival was 9.9 months (95% CI, 7.5–11.7). Thrombocytopenia (43%), neutropenia (24%), CNS symptoms (24%), asthenia (22%), and hemorrhage (14%) were the most common grades 3 and 4 adverse events. Four patients died due to “ascites, edema, bleeding, drowsiness, and hepatic encephalopathy.” The detailed causes of deaths are as yet not fully reported. Treatment efficacy analysis showed one 22 Targeted Therapies for Hepatocellular Carcinoma 359 confirmed partial response and stability of disease in 39% of the patients. A median treatment time of approximately 12 weeks likely reflects a too t oxic regimen at the chosen drug level. In another phase II study 34 patients with unresectable HCC received sunitinib at lower dose of 37.5 mg daily for 4 weeks followed by 2 weeks off [21]. Median overall survival was 9.9 months (95% CI, 7.5–11.7). Grades 3 and 4 adverse events included elevated SGOT (18%); lymphopenia (15%); neutropenia, thrombocytopenia, and fatigue (12%); elevated SGPT (9%); and hand-foot syndrome, rash, hyperbilirubinemia, and hypertension (6%). Nonetheless, the overall survival data of those two studies do not suggest superiority compared to sorafenib. Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) and has been shown to decrease HCC xenograft tumor models in mice [22]. This dual inhibition is partic- ularly attractive as fibroblast growth factor has been postulated to confer resistance to VEGF inhibition [17]. In a study evaluating brivanib as first- and second-line therapy in 96 patients with advanced HCC, there were limited responses. Median survival was 10 months in the treatment naïve cohort and was not reached in the second-line cohort [23]. Progression-free survival was 2.7 months in the treatment naïve group versus 2 months in the second-line group. The drug was well tolerated in the second-line setting [24]. ABT-869, a VEGF and PDGF inhibitor. ABT-869 was evaluated in a phase II study of 44 patients with HCC. Of the 44 patients, 38 were Child-Pugh A and 6 were Child-Pugh B. The Child-Pugh A patients median overall survival was 9.7 months and time-to-progression was 5.4 months. Tyrosine Kinase Inhibitors (TKIs) Epidermal growth factor receptor (EGF) signaling is active in precursor lesions of HCC such as fibrosis and cirrhosis. Varied EGFR ligands such as EGF, hepatocyte growth factor (HGF), transforming growth factor beta, and insulin growth factor (IGF) are involved in hepatocarcinogenesis making this pathway an attractive target for the treatment of HCC (Fig. 22.1). Several trials have explored the role of TKIs in HCC. Gefitinib is an oral EGFR tyrosine kinase inhibitor that blocks EGF-receptor 1, while lapatinib inhibits both EGFR-1 and EGFR-2 receptor. Both compounds have been studied in phase II trial, but given their limited efficacy further development as monotherapy is unlikely [25, 26]. Cetuximab, a monoclonal antibody targeted against the EGFR-1 receptor, has been studied in two phase II studies. While one study has reported an encouraging overall survival of 9.6 months [27], the earlier trial reported an unimpressive median TTP of 8 weeks [28]. Erlotinib is a selective inhibitor of the EGFR/HER-1-related tyrosine kinase enzyme. In an initial study, 38 patients with unresectable HCC were treated with erlotinib 150 mg daily on a continuous basis [29]. Median overall survival was 13 months. Grades 3 and 4 skin toxicity and diarrhea were the most notable adverse 360 J.W. Feilchenfeldt et al. events. A second independent phase II study treated 40 patients with erlotinib 150 mg with a median overall survival of 10.7 months [30]. Most notable s ide effects were diarrhea, fatigue, and AST elevation. As mentioned above, erlotinib has been explored in combination with bevacizumab in HCC [18] and this study will be reviewed in the next chapter. Management Issues Etiology In the Asia-Pacific study comparing sorafenib versus placebo described above [11], the statistically significant improvement (p = 0.014) did not reach the same magnitude of benefit as in the SHARP trial [4], despite the similarity in the hazard ratios of overall survival, progression-free survival, and time to progression. A possible explanation for these observed differences may be related to more advanced disease stage and lower performance status in patients from the Asia-Pacific study as compared to the SHARP trial [31]. Another explanation for the difference in outcome revolves around the etiology of HCC in those two studies. The majority of patients (73%) accrued on the Asia-Pacific study had hepatitis B as an underlying risk factor versus 18% of patients on the SHARP trial. In a retrospective evaluation of the large phase II trial evaluating sorafenib in patients with advanced HCC [9], N = 137, it was noted that hepatitis C positive patients had a longer time to progression of 6.5 months compared to 4 months (p = 0.05) for the patients with hepatitis B etiology [32]. Again there was a trend toward a survival advantage (p = 0.29) for the hepatitis C (12.4 months) versus hepatitis B patients (7.3 months). Similarly, a sub-group analysis from the SHARP has shown that patients with hepatitis C-based HCC treated with sorafenib (n = 93) had a median survival advantage of 14 months compared to the whole sorafenib treated group of 10.7 months, while the overall survival of the hepatitis C placebo arm compared to the placebo arm of the whole studied population was similar (7.9 months) [33]. These collective observations and in vitro data linking HCV infection to increased raf activity [34, 35] may explain a possible added advantage for patients with hepatitis C treated with sorafenib by addressing the root cause of the underlying liver dysfunction and predisposition to HCC. The outcome of the 18% of patients with hepatitis B-related HCC in the SHARP trial remains to be reported [36]. Overall for now, sorafenib has become a standard of care for patients with advanced HCC regardless of the etiology of their cancer; however, recognition exists for subsets potentially deriving greater or lesser benefit. Impact of Liver Function The results of the SHARP trial apply to patients with good to excellent performance status and Child-Pugh A score [4]; however, the safety and efficacy of sorafenib 22 Targeted Therapies for Hepatocellular Carcinoma 361 in patients with Child-Pugh B or C cirrhosis have yet to be defined. In a phase II study evaluating sorafenib in HCC [9], 28% of patients had Child-Pugh B cirrhosis. Pharmacokinetics for sorafenib were evaluated in 28 patients on the study and the AUC (0–8) (mg h/L) was comparable between the Child-Pugh A (25.4) and Child-Pugh B (30.3) patients. Cmax (mg/L) were 4.9 and 6 Child-Pugh A and B patients, respectively, with similar drug-related toxicity profiles. However, it was observed that the Child-Pugh B patients had worsening of their liver function more frequently [37]. An increase in bilirubin was reported in 40% of Child-Pugh B patients compared to 18% of Child-Pugh A. Eighteen percent of Child-Pugh B patients developed or had worsening ascites compared to 11% of Child-Pugh A. Emerging or worsening encephalopathy was reported in 11% of Child-Pugh B patients compared to 2% of Child-Pugh A. As sorafenib acts as a substrate for the UDP-glucuronosyltransferase UGT1A1, it remains unclear if the total bilirubin elevation observed is due to worsening liver function caused by a direct toxic effect of sorafenib, by a benign inhibitory effect of UGT1A1, or simply due to disease progression, or combination of these potential explanations. Direct bilirubin levels were not obtained in the original phase II study. Despite a shorter course of therapy for Child-Pugh B patients (12.9 weeks) compared to Child-Pugh A (24.9 weeks), sorafenib was discontinued or dose reduced at the same rates. Median time to progression for Child-Pugh A was 21 weeks (95% CI: 16–25 weeks) and Child-Pugh B 13 weeks (95% CI: 9–18 weeks). Overall survival for Child-Pugh A was 41 weeks (95% CI: 37–64 weeks) and 14 weeks for Child-Pugh B (95% CI: 12–26 weeks). Thus, Child-Pugh B patients fared worse than Child-Pugh A patients and had more frequent worsening of their cirrhosis. More data are needed to appropriately define the safety and efficacy of sorafenib in patients with HCC and Child-Pugh B liver function. In a phase I study evaluating two different doses of sorafenib in Japanese patients with advanced HCC [38], there were no substantial differences in the incidence of adverse events between Child-Pugh A and B groups. However, geometric means of AUC 0–12 and Cmax at steady state were slightly lower in patients with Child-Pugh B cirrhosis compared with Child-Pugh A. In 51 patients with solid and hematologic tumors and compromised liver or renal function, a phase I study of sorafenib did not report any apparent correlation with age or body weight [39]. More importantly deteriorating functional status of liver and renal parameters did not herald decreased clearance underscoring today’s empiric standard of practice as regards dosing of sorafenib. Suggested recommen- dations regarding dosing of sorafenib from this study are 400 mg twice per day for bilirubin up to 1.5 × upper limit of normal (ULN); 200 mg twice per day for bilirubin 1.5–3 × ULN; while no safe dose of sorafenib was established for bilirubin levels above 3 × ULN. In a recent manuscript detailing the FDA process of approval of sorafenib in HCC, Kane et al. referred to “the paucity of treatment options and variability in Child-Pugh scoring” as a reason for the broad approval for therapy by the FDA [40]; however, there has been a clear trend toward a restricted use of sorafenib for patient with Child-Pugh A and low B only [41–43] also highlighted by the recent 362 J.W. Feilchenfeldt et al. more restricted approval of sorafenib solely for HCC patients with Child-Pugh A by the Canadian authorities [44]. Tumor Assessment The importance of complete and partial tumor response is based on the assump- tion that volume reduction is a surrogate for treatment efficacy, i.e., prolongation of overall survival. RECIST and WHO classification are two commonly employed sys- tems designed to quantitate tumor volume [45]. With the clinical success of targeted therapy achieving meaningful clinical benefit even in absence of tumor volume alterations, classic evaluation parameters may seem inadequate to assess treatment efficacy. True objective responses in HCC patients treated with sorafenib are rare [4, 9, 11]. In the phase II trial with sorafenib [9], 33.6% of patients had stable disease (SD) for ≥16 weeks, and central “tumor necrosis” in response to sorafenib was frequently noted (Fig. 22.2). In a subset of 12 patients, tumor necrosis was evaluated based on analysis of computed tomography (CT) scans and correlated to treatment response [10]. The ratio of tumor necrosis and volume (TV/TN) was significantly associated with response, with responders (including stable disease) having greater increases in the ratio between necrosis and tumor volume relative to baseline, as compared to non-responders (p = 0.02), N/T was not significantly associated with overall survival. N/T as part of evaluating response needs to be prospectively evaluated and validated as part of a large clinical study. Fig. 22.2 Tumor necrosis (TN) was quantified with a semiautomated computerized technique on intravenous contrast-enhanced scans in 11 of 16 patients with HCC treated with sorafenib. Among the parameters studies, i.e., tumor volume (TV), necrosis (TN), and the TV/TN ratio solely TV/TN was correlated significantly to treatment response but not survival. Modified after Abou-Alfa GK et al. [7] 22 Targeted Therapies for Hepatocellular Carcinoma 363 This concept was further explored in a phase II study with the sunitinib [20]. Thirty-seven patients with unresectable HCC underwent assessment of antitumor activity using experimental parameters such as tumor density, volumetric measure- ment of percent tumor necrosis (VMTN), and intratumoral blood perfusion on monthly CT scan as compared to RECIST criteria. Decreased tumor density was observed in 68% of patients and activity assessed by VMTN showed minor (<50%) and major (= 50%) post-treatment tumor necrosis in 25 and 46% of patients, respectively. The authors concluded that tumor necrosis equal to 50% observed in 46% of patients receiving sunitinib suggested significant antitumor activity. These findings highlight the potential value of using tumor necrosis as a therapeutic monitoring tool which is feasibly translated to routine clinical practice. Contrast-enhanced imaging techniques such as dynamic contrast enhanced (DCE)-MRI may provide additional information to better characterize and differ- entiate responders from non-responders. In the previously discussed phase II trial of sunitinib in HCC [21], DCE-MRI analyses were performed serially to measure modifications in vascular permeability (K trans ). There were reported decreases in this surrogate marker of angiogenic activity; however, correlation to response and outcome is awaited. Similarly, as part of the phase II trial studying the anti-VEGFR agent, bevacizumab in HCC patients, DCE-MRI was performed before and after 8 weeks of treatment in eight patients and a significant decrease in enhancement was noted in seven out of eight patients [16]. The fact that a significant correlation was reported with reduction in tumor diameter speaks, however, against a represen- tative effect in a disease where tumor reduction is a very rare event. Larger studies are required to evaluate the significance of the observed findings. Ultrasound, a non-invasive imaging modality which allows dynamic assessment of blood flow in a quantitative manner and in combination with contrast agents such as micro-bubbles, has further refined quantification of blood flow [ 46]. Exploiting this technology, 48 patients with HCC treated with bevacizumab every 2 weeks were followed by dynamic contrast enhanced (DCE)-US. DCE-US was performed pre-treatment and at days 3, 7, 15, and 2 months after SonoVue R (Bracco) bolus injection. Predefined flow parameters were measured [47]. Patients were catego- rized into good and poor responders according to the clinical benefit after 4 months based on RECIST criteria (good responders = partial response plus stable disease). Quantitative functional evaluation by DCE-US performed at day 3 and day 8 report- edly predicted the response to treatment at 4 months. Although preliminary these results, if validated in a multicenter setting, might constitute an attractive tool to tailor treatment to responders and shield patients from unwanted and sometimes significant side effects right at the start of therapy. Computed tomographic (CT) perfusion is a similar technology that allows quantitative assessment of tumor blood flow (BF), blood volume (BV), mean transit time (MTT), and permeability surface area product (PS) [48]. In a feasibility study, 30 patients with unresectable or metastatic HCC underwent two CT perfusion imaging examinations within 30 h. The observed difference in perfusion between tumor tissue and normal liver was significantly different and there was a good correlation between repeated exams (r = 0.9, p < 0.01), underscoring the reproducibility 364 J.W. Feilchenfeldt et al. of this new technology. Perfusion CT was further explored in a phase II trial of HCC patients with bevacizumab in combination with oxaliplatin and gemcitabine [49]. CT scans were performed at baseline and 10–12 days thereafter. Among the parameters studied, mean transit time (MTT) allowed prediction of clinical outcome. Responders were separated from non-responders on the basis of stable disease or response versus disease progression. When comparing baseline perfusion parameters to outcome, MTT was decreased in the group with worse clinical outcome. Studies exploring this technology further in HCC patients undergoing treatment are eagerly awaited to better evaluate the clinical use of this technology. New Drug Development As we continue to learn more about the molecular pathogenesis of HCC, new drugs for new targets continue to be developed. Up-regulation of IGF-II, which occurs in 40% of HCC, has stimulated interest in its role as a potential target in HCC. IGF-II may target to the tyrosine kinase IGF-I receptor or the insulin receptor isoform A [50]. An IGF-1R antagonist is currently being studied in a phase II clinical trials in HCC. Angiopoietin-2 (Ang-2) has been reported to be overexpressed in HCC [51]. This and other recent observations suggest the study of angiopoietin-2 inhibiting strategies in HCC. A phase II study evaluating AMG-386, an antiangiogenic therapy that provides potent and selective inhibition of angiopoietins [52], in HCC i s planned. The reported role of hepatocyte growth factor in HCC and its interaction with other relevant pathways in hepatocellular carcinogenesis such as EGF or IGF pathway have stimulated interest in this growth factor. In an exploratory study, RNA expression of HGF and its receptor c-met were measured in resected HCC tumor tissue and corresponding normal tissue. Despite a preferential overexpression of c-met in this early-stage resected disease setting, there was no correlation with overall survival [53]. Given persuasive animal data using NK4, a hepatocyte growth factor antagonist which showed antitumoral activity in an HCC xenograft model [54], clinical trials with c-met inhibitors in humans are ongoing to define its role in HCC. Hedgehog (Hh) responsive tumors have been shown to spontaneously arise under circumstances where chronic liver injury and cirrhosis occur [55]. Exploratory studies of this pathway and its inhibitors, e.g., GDC0446 [56] are underway. This is to name a few. On the other hand, several large randomized clinical trial efforts are underway evaluating new targeted therapies’ single agents against the standard of care sorafenib. These include the evaluation of brivanib versus sorafenib, ABT-869 versus sorafenib, and sunitinib versus sorafenib. The latter phase III trial comparing sunitinib to sorafenib was closed prematurely, because of higher incidence of adverse events in the sunitinib arm. The study also did not meet criteria to demonstrate survival superiority or non-inferiority to sorafenib [57]. . Chapter 22 Targeted Therapies for Hepatocellular Carcinoma Jonas W. Feilchenfeldt, Eileen M. O’Reilly, Costantine Albany, and Ghassan K. Abou-Alfa Keywords HCC targeted therapies ·. progression was 4.2 months and the median overall survival was 9.2 months. The main drug-related grades 3 and 4 adverse effects were diarrhea (8%), hand- foot skin reaction (5.1%), and fatigue (9.5%) arm. Grades 3 and 4 side effects included diarrhea (8%) and hand-foot syndrome (8%). Bleeding was a rare event. The Asia-Pacific trial is a multicenter phase III, double-blind trial randomly assigning