22 Targeted Therapies for Hepatocellular Carcinoma 365 Summary Single-agent therapies for advanced HCC have been studied extensively. Thus far, sorafenib has been approved as a standard of care. Several studies evaluating other antiangiogenic agents, tyrosine kinase inhibitors, and multi other targets are at var- ied phases in their development. Other than defining the clinical activity of these agents, several studies are also contributing to a better understanding of HCC in regard to etiology, extent of liver failure, and radiologic tumor assessment. References 1. Thorgeirsson SS, Huber BE, Sorrell S, Fojo A, Pastan I, Gottesman MM (1987) Expression of the multidrug-resistant gene in hepatocarcinogenesis and regenerating rat liver. Science 236:1120–1122 2. Lopez PM, Villanueva A, Llovet JM (2006) Systematic review: evidence-based management of hepatocellular carcinoma—an updated analysis of randomized controlled trials. Aliment Pharmacol Ther 23:1535–1547 3. 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Sicklick JK, Li YX, Jayaraman A, Kannangai R, Qi Y, Vivekanandan P et al (2006) Regulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis 27:748–757 56. LoRusso PM, Rudin CM, Borad MJ, Vernillet L, Darbonne WC, Mackey H et al. (2008) First- in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors. J Clin Oncol 26(Suppl 15S):3516 [Abstract] 57. http://media.pfizer.com/files/news/press_releases/2010/sun_1170_042210.pdf Chapter 23 The Future: Combination Systemic Therapy for Hepatocellular Carcinoma Ahmed O. Kaseb and Melanie B. Thomas Keywords HCC systemic therapy · Carcinogenic pathways in HCC · Growth factors · Combination systemic therapy · SHARP trial · EGFR and VEGF path- ways · Sorafenib Introduction Hepatocellular carcinoma (HCC) is a potentially curable tumor by surgical resec- tion, local ablation, or liver transplantation. However, the majority of patients with HCC present with advanced stage disease, which is most commonly, accompanied by severe background liver disease. Hence, curative treatments are feasible for only a small fraction of patients with localized disease. The emergence of chemother- apy in the 1950s has led to the availability of systemic therapies for patients with hematologic malignancies and advanced solid tumors. However, systemic cytotoxic therapies have demonstrated a very limited impact on the natural history of advanced HCC. In addition, molecular characterization of hepatocarcinogenesis has led to the recognition of defined aberrant signaling pathways which helped in subsequent development of targeted agents as potential choices for the treatment of HCC, when used alone or in combination. The approval of the oral anti-cancer agent sorafenib (Nexavar R ) for the treat- ment of patients with HCC i n 2007 in both the United States and the European Union [1] represented a significant step forward in providing effective therapeu- tic options for the many individuals with advanced HCC. Prior to this exciting paradigm shift, HCC was regarded as a chemo-refractory, resistant tumor, and a sense of skepticism of ever developing effective systemic therapy for HCC, per- vaded the field. Over the course of the previous decades, numerous clinical trials A.O. Kaseb (B) Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 369 K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma, DOI 10.1007/978-1-60327-522-4_23, C Springer Science+Business Media, LLC 2011 370 A.O. Kaseb and M.B. Thomas of a wide variety of chemotherapeutic and hormonal agents had shown little or no activity in this complex malignancy [2]. Despite the fact that sorafenib does not yield radiographic tumor shrinkage, the traditional measure of anti-tumor activity, it clearly does impact carcinogenic activity in HCC, based on prolongation of both time to tumor progression and overall survival [3]. The demonstration of improved patient outcome of a targeted chemotherapeutic agent in this very challenging malig- nancy has also generated renewed enthusiasm in the field and an explosion of clinical research efforts in HCC worldwide. Sorafenib also provides a platform on which to build future comparative, adju- vant, and combination clinical trials to further improve patient outcome. The challenge going forward is to i dentify those agents that in combination with sorafenib have the greatest potential for improved efficacy while ensuring patient safety. Combination Systemic Therapy for Hepatocellular Carcinoma In recent years, several molecular “targets” including oncogenes, oncoproteins, and cellular receptors have been identified in a variety of cancers as being key elements in carcinogenic pathways. Hepatocarcinogenesis is a complex multistep process, which results in a large number of heterogeneous molecular abnormal- ities [4–8], and thus offers numerous potential targets for existing therapeutic agents. Consequently several agents that target a variety of pathways are rational choices for combination therapy in HCC. Clearly sorafenib is now established as an effective targeted agent in HCC. The future of successful systemic therapy in HCC is to improve upon the survival benefit of sorafenib by developing rational, effective combination regimens. Possible regimens include combining traditional cytotoxic agents, biologic agents that target other carcinogenic pathways, or both, with sorafenib. Ideally, preclinical data exist or will be developed, that confirms additive anti-cancer activity, to provide rationale for designing clinical trials of combinations. Further, development of strategies to “validate” the role of a partic- ular molecular target in HCC, and surrogate markers of whether binding that target results in clinical efficacy, are desirable. Unfortunately, such data are elusive in even much more well-characterized tumors. Notably, angiogenesis is an essential step in the growth and spread of HCC. Inhibiting angiogenesis would therefore seem to be a reasonable approach to prevent or treat HCC. However, tumor neovessels differ from normal vasculature in that they are tortuous, irregular, and hyperpermeable. These abnormalities result in irregular blood flow and increased interstitial pres- sure inside the tumor, which can impair the delivery of oxygen (a known radiation sensitizer) and drugs to cancer cells. Emerging evidence suggests that antiangio- genic therapy can normalize the structure and function of the tumor neovasculature, thereby improving drug delivery. This normalization effect may underlie the ther- apeutic benefit of combined antiangiogenic and cytotoxic therapies as evident in colorectal cancer studies [9]. 23 The Future: Combination Systemic Therapy for Hepatocellular Carcinoma 371 In some malignancies, the molecular target–targeted agent relationship is well understood, for example, the monoclonal antibody trastuzumab (Herceptin R )is only effective in tumors in which the her-2/neu oncoprotein is amplified. Conversely, there are several agents that target the transmembrane epidermal growth factor receptor (EGFR) and have demonstrated survival benefit in a broad range of tumor types, yet little is understood regarding the relationship between “target” expression and agent efficacy or lack thereof. Further, bevacizumab is a recombinant humanized monoclonal antibody that binds VEGF-A and targets tumor-associated angiogenesis by preventing receptor binding and has shown improved patient survival in multi- ple tumor types, yet a confirmed measurable relationship between target expression, binding, and activity remains to be described. Table 23.1 summarizes evidence that describes the status of target “validation” in a variety of malignancies. Key Carcinogenic Pathways in HCC The PI3K/Akt/mTOR pathway (phosphoinositide-3 kinase/protein kinase B/mammalian target of rapamycin) is responsible for cellular proliferation and apoptosis and is closely linked to cell cycle. PI3K is associated with cell surface growth factor receptors and upon ligand binding can trigger formation of PIP3, which in turn activates Akt and leads to a number of downstream events (mTOR being one of the targets) [10, 11]. This pathway is upregulated in a subset of HCC patients. Molecular targeted therapy such as rapamycin, a naturally occurring mTOR inhibitor, showed promising results in HCC cell lines [12, 13–15]. However, published results from clinical trials of agents that target MTOR in HCC patients are available in abstract form only [16–19]. The Ras–raf kinase pathway is also dysregulated in HCC and Ras-pathway acti- vation is nearly ubiquitous in human HCC. This is an important regulatory pathway for cell growth, survival, and migration and is highly regulated by activators and inhibitors. The related Jak/Stat pathway is also activated by growth factors and cytokines involved in cell differentiation, proliferation, apoptosis. Both pathways are activated in majority of HCC tissue compared to non-cancerous liver, pos- sibly by loss of inhibition. The protein RKIP (Raf kinase inhibitory protein) is downregulated in human HCC. Growth Factors as Therapeutic Targets in HCC There is extensive evidence for growth factor dysregulation in HCC (Table 23.2). The epidermal growth factor receptor (EGFR) is frequently expressed in human HCC cell cultures and EGF may be one of the mitogens that are needed for cellu- lar proliferation. Several agents that inhibit EGF signaling are clinically available, including gefitinib, cetuximab, erlotinib and panitumumab. Erlotinib is an orally 372 A.O. Kaseb and M.B. Thomas Table 23.1 Select targeted anti-cancer agents Agent Target Tumor type Effect Target Validated? Trastuzumab Lapatinib HER2 receptor HER1-2 heterodimers HER2- overexpressing breast cancer Improves survival Decreases recurrence as adjuvant therapy Yes Bevacizumab mAB binds serum VEGF-A ligand Metastatic colorectal, lung, breast cancers Improves survival, TTP in metastatic colon, lung, breast cancers No Cetuximab (EGFR mAb) Extra-cellular domain EGFR Irinotecan- refractory colorectal cancer Improves survival, TTP in metastatic colon Yes: Kras mutants do not benefit from EGFR mAb Gefitinib Erlotinib (EGFR TKI) Intracellular phosphorylation site NSCLC pancreatic Improves survival NSCLC, 2nd line Improves PFS in pancreatic ca by <2 wks EGFR mutations in minority of NSCLC patients predict benefit Sorafenib Raf–ras pathway, VEGF RCC, HCC Improves survival, TTP No Sunitinib Raf–ras pathway, VEGF GIST RCC Improves survival and TTP No Bortezomib mTOR Myeloma Improves survival Decreases transfusions No Imatinib C-kit, PDGF GIST CML Improves RR, survival Decreases recurrence Yes HER, human epidermal growth factor receptor; mAB, monoclonal antibody; VEGF, vascular endothelial growth factor receptor; TTP, time to progression; EGFR, epithelial growth factor receptor; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; HCC, hepatocellular carcinoma; mTOR, mammalian target of rapamycin; RR, response rate; PDGF, platelet-derived growth factor; GIST, gastrointestinal stromal tumor; CML, chronic myelocytic leukemia active and selective inhibitor of the EGFR/HER1-related tyrosine kinase enzyme. EGFR/HER1 expression was detected in 88% of the patients in a Phase II study of erlotinib [20]. In two Phase II studies of this agent, the response rates were less than 10% but the disease control rate was more than 50%, and median survival times were 10.7 and 13 months, respectively [20, 21]. 23 The Future: Combination Systemic Therapy for Hepatocellular Carcinoma 373 Table 23.2 Potential therapeutic targets in HCC Factor Mechanism Expression in HCC VEGF (angiogenesis) • HCC highly vascular tumors • Early vascular invasion; negative prognostic factor • VEGF – known mitogen for hepatocytes • Frequency of vascular invasion is higher in HCC patient with high serum VEGF levels than low VEGF levels • Highly prevalent in HCC • Increases with cell differentiation • VEGF gene is transcribed by HCC cells • VEGF protein produced by HCC cells • Neovascularization begins with precursor dysplastic nodules, progresses through HCC IGF family Common in fetal liver; declines after birth Highly prevalent in HCC Platelet-derived growth factor (PDGF) Cell membrane receptor involved in proliferation, migration, blood vessel formation • Highly expressed in liver • Induces fibrosis, steatosis, HCC • Links TGFβ to β-catenin accumulation Fibroblast growth factor (FGF) Involved in tumor neoangiogenesis Over expression common in fibrosis, cirrhosis, HCC HGF (hepatocyte growth factor) Known pro-angiogenic growth factor, acts via c-met • Commoninhepatocyte regeneration • Expressed by hepatic stellate cells and myofibroblasts EGF (epidermal growth factor receptor) • Known mitogen in multiple tumor types Increases HCC cell line proliferation • Common in chronic hepatitis, cirrhosis and HCC (40–80%) • erbB2 expression variable (11–80%) TGFα (transforming growth factor) TGFβ/EGFR Upregulates DNA synthesis Mitogenic for hepatocytes Interacts with EGFR Up regulated in 40% • Frequent in hepatitis, cirrhosis, HCC; not in normal liver. • Expression in 80% of all HCCs • Potent stimulator of hepatocellular DNA synthesis, mitogenic HCCs are generally hypervascular, and vascular endothelial growth factor (VEGF) promotes HCC development and metastasis. Various agents targeting the VEGF circulating ligand or transmembrane receptor, including bevacizumab (Avastin R ), sorafenib (Nexavar R ), and TSU-68, have been studied in patients with HCC. Bevacizumab, a monoclonal antibody inhibitor of VEGF ligand, has been investigated in Phase II studies alone or in combination with other agents. 374 A.O. Kaseb and M.B. Thomas These studies showed a high disease control rate of over 80% and a median PFS of more than 6 months [22, 23]. Sorafenib, an oral multikinase inhibitor, blocks tumor cell proliferation mainly by targeting Raf/MEK/ERK signaling at the level of Raf kinase and exerts an antiangiogenic effect by targeting VEGFR-2/-3. TSU-68 is an oral antiangiogenesis compound that blocks VEGFR-2 (vascular endothe- lial growth factor receptor), PDGFR (platelet-derived growth factor receptor), and FGFR (fibroblast growth factor receptor); a Phase I/II study has been conducted in Japan. Existing Evidence for Benefit from Combination Systemic Therapy in HCC There is much to be learned from the recent history of the development of combi- nation targeted therapy in other solid tumors. For example, early Phase II clinical trials of the combination of bevacizumab and erlotinib in advanced renal cell car- cinoma (RCC) showed improved survival; however, in a larger randomized trial the difference in outcome from the combination therapy did not provide additional clinical benefit compared with bevacizumab alone [24–29]. Among the most effica- cious combination therapies in solid tumors are those that have been developed in metastatic colorectal cancer. The addition of cetuximab (Erbitux R ) to irinotecan- based chemotherapy and bevacizumab to 5-fluorouracil-based chemotherapy sub- stantially prolonged patient survival in multiple studies [30–35]. Following the success of combination cytotoxic and biologic therapies in colorectal cancer, sev- eral trials were designed to assess the benefits of combining both biologics, erbitux and bevacizumab, with cytotoxic chemotherapy. Unfortunately, it was found that the combination resulted in excess toxicity and the trial was stopped early [36]. Similarly a Phase I clinical trial of the combination of sorafenib and bevacizumab in patients with solid tumor showed promising clinical activity, even in patients with refractory tumors, but significant toxicity requiring dose reductions in a sig- nificant majority of patients [37]. While the side effect profile of targeted agents in general is more favorable than traditional cytotoxic therapy, these agents are not benign and combinations must be studied in a step-wise fashion to maintain safety. Notably, interaction between the EGFR and the VEGF pathways is well known. EGFR and VEGF share common downstream signaling pathways, and several pre- clinical studies have provided evidence for either direct or indirect angiogenic effects of EGFR signaling. In addition, direct EGFR angiogenic effects have been demonstrated by Hirata et al. [38]. Furthermore, in preclinical models, upregulation of VEGF has been implicated in resistance to EGFR inhibition [39]. Therefore, sev- eral clinical trials in different types of cancers combined anti-VEGF plus anti-EGFR [40]. Our trial was the first to report the clinical activity and confirm the tolerability . Systemic Therapy for Hepatocellular Carcinoma Ahmed O. Kaseb and Melanie B. Thomas Keywords HCC systemic therapy · Carcinogenic pathways in HCC · Growth factors · Combination systemic therapy. open-label study of cetuximab in unresectable hepatocellular carcinoma: final results. J Clin Oncol 25(Suppl 18S):4598 22 Targeted Therapies for Hepatocellular Carcinoma 367 29. 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