Targeted agents for second-line treatment of advanced hepatocellular carcinoma

Over the past ten years, sorafenib, a multikinase inhibitor, has been the standard of care for patients with unresectable hepatocellular carcinoma (HCC) and well-preserved liver function. Recently, lenvatinib, a different multikinase inhibitor, was shown to be non-inferior to sorafenib, in terms of survival, while all other agents previously tested failed to prove non-inferiority (or superiority) when compared to sorafenib. Similarly, in the second-line setting, most investigational drugs failed to provide better survival outcomes than placebo. However, in the last 2 years three positive phase III trials have been published in this setting. The RESORCE trial, a phase III study evaluating regorafenib in HCC patients who experienced disease progression after first-line treatment with sorafenib, showed better outcomes with regorafenib compared to placebo. More recently, the phase III CELESTIAL trial demonstrated the superiority of cabozantinib, a multikinase inhibitor targeting vascular endothelial growth factor receptor, MET, and AXL, vs placebo in the second- and third-line setting in patients progressing on or intolerant to sorafenib. The survival benefits of a sustained anti-angiogenic inhibition were demonstrated also with ramucirumab in the phase III REACH-2 trial in patients previously treated with sorafenib and who had high baseline alpha-fetoprotein levels. Overall, the adverse events reported in these trials were in line with the known safety profiles of the tested agents. After nearly a decade of a certain degree of stagnation, we are now witnessing a period of novel therapeutic advances with multikinase inhibitors and monoclonal antibodies that will likely change the treatment scenario of HCC.     

Molecularly targeted therapy for advanced hepatocellular carcinoma in 2012: current status and future perspectives

Improving the overall survival for patients with advanced hepatocellular carcinoma (HCC) requires development of effective systemic therapy. Despite the successful approval and extensive application of sorafenib, the prognosis for patients with advanced HCC remains poor and the benefits with sorafenib are modest. In the past few years, there have been renewed and continued interests and active research in developing other molecularly targeted agents in HCC. While the initial efforts are focusing on anti-angiogenic therapy, other agents targeting the epidermal growth factor-receptor, mammalian target of rapamycin (mTOR), hepatocyte growth factor/c-Met among others have entered HCC clinical trials. Combining different molecularly targeted agents or combining targeted agents with chemotherapy represent other strategies under investigation. This review will attempt to summarize the current status of other molecularly targeted agents or regimens beyond sorafenib under development in advanced HCC and the future perspectives.     

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.     

Sorafenib and DE605, a novel c-Met inhibitor,synergistically suppress hepatocellular carcinoma

Sorafenib, an oral multikinase inhibitor of Raf, VEGF and PDGF receptor signaling is approved for advanced hepatocellular carcinoma (HCC). One strategy to improve HCC therapy is to combine agents that target key signaling pathways. Aberrant mesenchymal-epithelial transition factor (c-Met) activation is associated with a variety of human malignancies and therefore represents a target for therapy. In this study, we investigated a novel c-Met inhibitor, DE605, together with sorafenib in hepatocellular carcinoma cells in vitro and in vivo. DE605 and sorafenib synergistically induced apoptosis in hepatocellular carcinoma cells. Mechanistically, DE605 activated the FGFR3/Erk pathway, which in turn was inhibited by sorafenib, resulting in synergism. Finally, DE605 and sorafenib significantly inhibited growth of PLC/PRF/5 hepatocellular carcinoma tumor xenografts in athymic nude mice. Importantly, no obvious weight loss (toxicity) was detected. Thus in combination, DE605 and sorafenib target complementary anti-apoptotic pathways and synergistically suppress HCC, providing the rationale for clinical studies with this novel combination.     

Hepatocellular Carcinoma: Review of Targeted and Immune Therapies

Background

Hepatocellular carcinoma is the fifth most common cancer globally and the second leading cause of cancer-related mortality worldwide. Despite the established efficacy of screening programs for at-risk individuals, most patients are diagnosed at later stages of disease, wherein the tumor characteristics or liver disease progressions do not allow for curative interventions. Many cytotoxic chemotherapeutic agents have been tested in patients with advanced disease with disappointing outcomes and poor tolerance; therefore, no standard systemic therapy emerged until the approval of sorafenib in 2006.

Conclusion

Despite the toxicity and low response rate, sorafenib had shown a significant survival benefit in phase III clinical trials, thus encouraging clinical research aimed at advancing the field of molecular therapy. Disrupted signaling pathways related to hepatocellular carcinoma (HCC) include the Wnt/β-catenin, Ras/Raf/MAPK, phosphatidyl inositol 3-kinase/Akt/mechanistic target of rapamycin, hepatocyte growth factor/c-mesenchymal–epithelial transition, IGF, vascular endothelial growth factor, and platelet-derived growth factor pathways, and a variety of agents targeting these pathways are currently under investigation. Additionally, better comprehension of the complex mechanisms underlying the ability of tumor cells to escape immune surveillance has led to impressive results with immunotherapy in many types of cancer, and this treatment strategy is currently being developed for HCC patients. Previous and ongoing targeted therapy and immunotherapy trials for HCC are discussed in this review.

     

Metastatic melanoma: scientific rationale for sorafenib treatment and clinical results

In advanced metastatic melanoma (AJCC stage IV), the prognosis is still poor, and views differ on the appropriate systemic treatment for these patients. Therefore, new approaches in therapeutic regimens are mandatory. Sorafenib is an oral multikinase inhibitor that targets 2 classes of kinases which are known to be involved in both tumor proliferation and angiogenesis. These kinases include Raf kinases and the vascular endothelial growth factor (VEGF) receptor. Sorafenib has been evaluated as a single therapy agent as well as in combination with various chemotherapeutical drugs in a number of clinical trials. The vast majority of clinical data exists for patients with advanced renal cell cancer for which sorafenib has been approved by the FDA and EMEA. Very recently, sorafenib was approved for advanced hepatocellular cancers due to its overall survival improvement. Since B-raf gene mutations have been found in 69% of melanoma cell lines, sorafenib was brought into various phase I/II and phase III trials in metastatic melanoma. However, as a single-agent therapy, sorafenib seems to be of limited use. Also, the combination of sorafenib with the chemotherapeutic agents carboplatin and paclitaxel has failed to show superiority in progression-free and overall survival compared to the same chemoregimen plus an oral placebo in a phase III trial (PRISM study). More promising data were observed in large-sized phase II studies on dacarbazine (DTIC) plus sorafenib and temozolomide plus sorafenib. However, these data need to be confirmed in prospective randomized phase III trials. Till then, sorafenib remains an interesting but still experimental new agent for melanoma.     

Investigational agents in the management of non-small cell lung cancer

Novel therapeutic agents are playing an increasingly prominent role in the treatment of non-small cell lung cancer (NSCLC). Drugs that target important oncogenic proteins or pathways, whether used as monotherapy or in combination with established regimens, have largely supplanted traditional cytotoxic agents in modern clinical trials. In particular, inhibitors of the epidermal growth factor receptor (EGFR) and/or vascular endothelial growth factor (VEGF) pathways have shown significant clinical activity and in some cases have changed the standard of care for advanced NSCLC. In the past year, an unprecedented number of trials have been reported using agents targeting the EGFR (erlotinib, gefitinib, cetuximab), VEGF (bevacizumab) or the VEGF receptor (sorafenib, sunitinib, cediranib), and inhibitors of both pathways (vandetanib, erlotinib, or cetuximab plus bevacizumab). This review focuses on recently reported trials of targeted agents that have the potential to affect the treatment of patients with NSCLC.     

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.     

Clinical significance of MET in gastric cancer

Chemotherapy has become the global standard treatment for patients with metastatic or unresectable gastric cancer (GC), although outcomes remain unfavorable. Many molecular-targeted therapies inhibiting signaling pathways of various tyrosine kinase receptors have been developed, and monoclonal antibodies targeting human epidermal growth factor receptor 2 or vascular endothelial growth factor receptor 2 have become standard therapy for GC. Hepatocyte growth factor and its receptor, c-MET (MET), play key roles in tumor growth through activated signaling pathways from receptor in GC cells. Genomic amplification of MET leads to the aberrant activation found in GC tumors and is related to survival in patients with GC. This review discusses the clinical significance of MET in GC and examines MET as a potential therapeutic target in patients with GC. Preclinical studies in animal models have shown that MET antibodies or small-molecule MET inhibitors suppress tumor-cell proliferation and tumor progression in MET-amplified GC cells. These drugs are now being evaluated in clinical trials as treatments for metastatic or unresectable GC.     

Indonesian consensus on systemic therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a deadly cancer with a rising incidence in the last 20 years. Most patients are diagnosed late when curative treatment is no longer feasible. With the background of chronic liver disease in most patients, the management of HCC becomes more complicated, in which well-preserved liver function is a prerequisite for locoregional or systemic therapies. In 2008, sorafenib became the first systemic agent proven to provide survival benefit for patients with advanced-stage HCC. For nearly a decade, no treatment has succeeded in providing better results than sorafenib. However, numerous advances in systemic therapies have emerged in the last 5 years to fulfill the unmet needs of effective therapeutic options. Several agents have been approved for clinical use after positive results in phase III clinical trials, including lenvatinib, regorafenib, cabozantinib, ramucirumab, and lastly immune checkpoint inhibitor atezolizumab in combination with bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor. With various options available, knowledge on the clinical evidence of each drug, their safety profile, as well as the patient characteristics and preferences become mandatory in clinical decision making. The objective of this consensus is to help clinicians, health-care workers, and policy makers in providing best clinical care for HCC patients.     

Novel Agents on the Horizon for Cancer Therapy

Although cancer remains a devastating diagnosis, several decades of preclinical progress in cancer biology and biotechnology have recently led to successful development of several biological agents that substantially improve survival and quality of life for some patients. There is now a rich pipeline of novel anticancer agents in early phase clinical trials. The specific tumor and stromal aberrancies targeted can be conceptualized as membrane‐bound receptor kinases (HGF/c‐Met, human epidermal growth factor receptor and insulin growth factor receptor pathways), intracellular signaling kinases (Src, PI3k/Akt/mTOR, and mitogen‐activated protein kinase pathways), epigenetic abnormalities (DNA methyltransferase and histyone deacetylase), protein dynamics (heat shock protein 90, ubiquitin‐proteasome system), and tumor vasculature and microenvironment (angiogenesis, HIF, endothelium, integrins). Several technologies are available to target these abnormalities. Of these, monoclonal antibodies and small‐molecule inhibitors have been the more successful, and often complementary, approaches so far in clinical settings. The success of this target‐based cancer drug development approach is discussed with examples of recently approved agents, such as bevacizumab, erlotinib, trastuzumab, sorafenib, and bortezomib. This review also highlights the pipeline of rationally designed drugs in clinical development that have the potential to impact clinical care in the near future. CA Cancer J Clin 2009;59:111–137. © 2009 American Cancer Society, Inc.     

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.     

Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) show limited sensitivity to cytotoxic agents, requiring the search for novel therapies. Recently, data from a phase III trial demonstrated that sunitinib produces a clinically significant improvement in progression-free survival in patients with unresectable, advanced, or metastatic GEP-NETs. Based on this finding, sunitinib became the first targeted drug approved for the treatment of GEP-NETs, paving the way for the approval of other anticancer agents in this drug-orphan disease. To date, results of trials involving other multitargeted tyrosine kinase inhibitors, such as sorafenib, the monoclonal antibody bevacizumab, and insulin-like growth factor 1 receptor inhibitors, have also shown promising results, and some are already being studied in phase III trials. This review updates the results of ongoing trials using inhibitors of growth factors and tyrosine kinase receptors involved in the carcinogenesis of GEP-NETs.     

Molecular targeted therapies for cancer: sorafenib mono-therapy and its combination with other therapies (review)

Sorafenib is an oral multikinase inhibitor that acts by inhibiting tumor growth and disrupting tumor microvasculature through antiproliferative, anti-angiogenic and proapoptotic effects. It exerts these effects via inhibition of multiple targets including Raf serine/threonine kinases, vascular endothelial growth factor receptor tyrosine kinases; VEGFR-1, VEGFR-2, VEGFR-3 and platelet-derived growth factor receptor?β (PDGFR-β). Current literature shows that the deregulated signaling through these receptors is commonly seen in human tumors. In addition, sorafenib is also shown to induce apoptosis through downregulation of Mcl-1 in many cancer types. Hence, sorafenib as a single agent has shown promising activity in some cancers such as renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and thyroid cancers. Currently, the drug holds FDA approval for the treatment of advanced RCC and unresectable HCC. However, many clinical studies have indicated several limitations to the application of sorafenib as a single agent in various other cancers. Owing to these reasons and the potential of sorafenib to synergize with other anticancer therapies, its combination with other targeted agents and chemotherapy has been widely explored with promising results. In addition, it has also shown synergistic results when combined with radiation. This review summarizes the current basic and clinical studies on the effects and mechanisms of sorafenib either administered alone or in combination with other anticancer treatments.     

Sorafenib: recent update on activity as a single agent and in combination with interferon-alpha2 in patients with advanced-stage renal cell carcinoma

Metastatic renal cell carcinoma does not respond favorably to conventional treatment strategies and is not very responsive to cytokine therapy. Therefore, novel targeted treatment approaches have been explored for patients with renal cancer who have chemotherapy-refractory disease. Sorafenib (BAY 43-9006) is a smallmolecule inhibitor that has been shown to target members of multiple classes of tyrosine kinases that are known to be involved in tumor cell proliferation and tumor angiogenesis. These kinases include vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor, Flt-3, c-kit, and Raf kinases. Based on the significant improvement in progressionfree survival, sorafenib received Food and Drug Administration approval in December 2005 for the treatment of renal cell carcinoma. In combination studies, sorafenib with other antitumor agents has demonstrated significant clinical activity in patients with renal cell carcinoma. As discussed in this mini-review, the clinical potency of sorafenib as a single agent or in combination with other antitumor agents is being evaluated in several ongoing clinical trials in patients with renal carcinoma.     

Sorafenib: Recent Update on Activity as a Single Agent and in Combination with Interferon-α2 in Patients with Advanced-Stage Renal Cell Carcinoma

Metastatic renal cell carcinoma does not respond favorably to conventional treatment strategies and is not very responsive to cytokine therapy. Therefore, novel targeted treatment approaches have been explored for patients with renal cancer who have chemotherapy-refractory disease. Sorafenib (BAY 43-9006) is a smallmolecule inhibitor that has been shown to target members of multiple classes of tyrosine kinases that are known to be involved in tumor cell proliferation and tumor angiogenesis. These kinases include vascular endothelial growth factor receptor (VEGFR)–1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor, Flt-3, c-kit, and Raf kinases. Based on the significant improvement in progressionfree survival, sorafenib received Food and Drug Administration approval in December 2005 for the treatment of renal cell carcinoma. In combination studies, sorafenib with other antitumor agents has demonstrated significant clinical activity in patients with renal cell carcinoma. As discussed in this mini-review, the clinical potency of sorafenib as a single agent or in combination with other antitumor agents is being evaluated in several ongoing clinical trials in patients with renal carcinoma.     

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.     

The realisation of targeted antitumour therapy

Better understanding of the pathways regulating proliferation and metastasis of cancer cells has led to the development of novel molecular-targeted therapies. The number of molecular-targeted agents approved for use in the clinic is growing, with many more in clinical trials. Most of these compounds can be broadly classified into two main categories: monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The pathological processes targeted include vascular endothelial growth factor-dependent tumour angiogenesis and epidermal growth factor receptor-dependent tumour cell proliferation and survival. Unlike conventional chemotherapy, molecular-targeted agents offer the potential advantages of a relatively high therapeutic window and use in combination with other anticancer strategies without overlapping toxicity. It is hoped that these drugs will become valuable therapeutic tools within the multimodal approach to treating cancer. Recent progress in targeted antitumour therapy is discussed, with a focus on antiangiogenesis.