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

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

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.     

What is the indication for sorafenib in hepatocellular carcinoma? A clinical challenge

The incidence of hepatocellular carcinoma is rising in many countries, including the United States. Approval of sorafenib (Nexavar) as the first targeted therapy for treatment of advanced hepatocellular carcinoma (HCC) represents a milestone in the treatment of this disease. The approval was based on two large randomized phase III trials from the Western and Eastern hemispheres that showed an overall survival benefit compared with placebo in patients with well-preserved liver function. The exact indication for sorafenib is unclear, however. The U.S. Food and Drug Administration (FDA) authorized use of sorafenib for "unresectable HCC", an indication which is very broad, vague, and confusing. Less is known about the effects of sorafenib in patients with decompensated liver disease, or of sorafenib in combination with local therapy or in a transplant setting. Prospective trials are lacking in these areas. We will review current data on use of sorafenib in HCC.     

Novel antiangiogenic therapies against advanced hepatocellular carcinoma (HCC)

Angiogenesis is a cornerstone in the process of hepatocarcinogenesis. In the sorafenib era, other antiangiogenic targeted drugs, such as monoclonal antibodies and a new generation of tyrosine kinase inhibitors, have been shown in phase II trials to be safe and effective in the treatment of advanced hepatocellular carcinoma. Several currently active phase III trials are testing these drugs, both in first- and second-line settings. Strategies to overcome primary and acquired resistance to antiangiogenic therapy are urgently needed. Novel biomarkers may help in improving the efficacy of drugs targeting angiogenesis.     

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.     

Targeted agents for the systemic treatment of advanced hepatocellular carcinoma

The prognosis for advanced hepatocellular carcinoma is poor and systemic therapy has historically been of limited benefit. However, novel targeted agents offer promise in improving patient outcomes. In a recent phase III study the oral multi-tyrosine kinase inhibitor sorafenib was demonstrated to have a survival advantage over a placebo in advanced hepatocellular carcinoma. Similar efficacy was demonstrated in a phase III trial limited to an Asian–Pacific group of patients. While these results are encouraging, it is vital to make further progress. In this review we examine current knowledge of targeted agents in advanced hepatocellular carcinoma. We also address some of the key issues that require exploration regarding the use of targeted agents in advanced hepatocellular carcinoma.     

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.     

Treatment of intermediate/advanced hepatocellular carcinoma in the clinic: how can outcomes be improved?

Hepatocellular carcinoma (HCC) is a complex condition associated with a poor prognosis. Treatment outcomes are affected by multiple variables, including liver function, performance status of the patient, and tumor stage, making a multidisciplinary approach to treatment essential for optimal patient management. Only ～30% of patients are eligible for curative therapies (surgery or ablation); palliative treatments include transcatheter arterial chemoembolization (TACE) and sorafenib. Treatment choice is guided by staging systems and treatment guidelines, although numerous systems exist and treatment guidelines vary by region. The current standard of care for patients unsuitable for potentially curative therapy is locoregional therapy with TACE. This treatment is associated with survival benefits, but there is no consensus regarding the optimum treatment/retreatment strategy. For patients with more advanced disease or who have failed locoregional therapy, sorafenib is the standard of care. Sorafenib is a targeted agent with proven survival benefits as monotherapy in these patients, and ongoing studies will clarify its role in combination with other agents and in patients with impaired liver function. Although other novel agents and therapeutic approaches are emerging, such as radioembolization and various targeted agents, further suitably designed randomized clinical trials (RCTs) comparing these agents with the standard of care are needed. In addition to RCTs, the collection of real-life data will also be important to allow physicians to make fully informed treatment decisions. The Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib (GIDEON) study is a global, noninterventional study of patients with unresectable HCC receiving sorafenib. The aim of that study is to compile a large robust database to evaluate local, regional, and global factors influencing the management of patients with HCC. It is hoped that findings from the GIDEON study along with phase III RCT data will lead to better outcomes for patients with intermediate-advanced HCC.     

Cabozantinib for the treatment of hepatocellular carcinoma

Introduction: The randomized, placebo-controlled, phase III CELESTIAL trial demonstrated statistically and clinically significant improvement in overall survival with cabozantinib in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. Most frequently reported adverse events included palmar-plantar erythrodysesthesia, hypertension, increased aspartate aminotransferase, fatigue, and diarrhea.

Areas covered: In this review we analyze and discuss preclinical and clinical data of cabozantinib. We summarize efficacy and safety results of phase II and III trials of cabozantinib in the treatment of patients with advanced HCC and we present ongoing trials of cabozantinib in combination with checkpoint inhibitors.

Expert opinion: Cabozantinib is a new second-line and the only third-line treatment for patients with advanced HCC, nevertheless some data are still missing to better inform clinical decisions on how to treat specific patient populations. Next trials designs will have to incorporate heavy efforts in terms of translational research to maximize the benefits of such treatments.     

Systemic Treatment of Patients with Advanced,Unresectable Hepatocellular Carcinoma: Emergence of Therapies

To date, sorafenib, a multiple tyrosine kinase inhibitor, is the only systemic agent approved by the FDA in the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Several other tyrosine kinase-inhibiting agents have been investigated in the first-line setting, either alone (sunitinib, brivanib, linifanib, and lenvatinib) or in combination with sorafenib (erlotinib and doxorubicin) in phase 3 trials. However, none of these studies demonstrated an improvement in survival over sorafenib. Many agents have also been tested in patients with HCC whose disease has progressed on sorafenib, but regorafenib is the only one to have demonstrated efficacy in this setting in a randomized, phase 3 trial. There were no clear survival benefits shown with everolimus, brivanib, or ramucirumab as second-line therapy. Nivolumab has also shown promising efficacy in patients with HCC who progressed on sorafenib, which was recently granted approval by the FDA, although larger confirmative trials may be considered. The treatment landscape for patients with advanced unresectable hepatocellular tumors has remained fairly static for the past 10 years, with multiple failed trials yield little change in the way these patients might be treated. However, recent findings for regorafenib, lenvatinib, and nivolumab have led to the most significant changes in the treatment paradigm in years.     

Antiangiogenic therapy for ovarian cancer

PURPOSE OF REVIEW: To highlight the current antiangiogenic compounds being evaluated as single agents or in association with chemotherapy in the treatment of ovarian cancer, as well as the rationale for their development. RECENT FINDINGS: Several proangiogenic factors may be potential targets for antiangiogenic therapy in ovarian cancer. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been evaluated as a single agent in two phase II clinical trials and in combination with chemotherapy in three phase II studies, with promising results. This agent is also being evaluated in association with chemotherapy in two phase III clinical trials, both in the treatment and in the maintenance settings. Heparanase inhibitors and inhibitors of platelet-derived growth factor signalling remain as potential agents to be investigated in phase II trials. The development of biomarkers to define appropriate dosing regimens and predict which patients may benefit from antiangiogenic therapies is of great importance. SUMMARY: Data from preclinical and clinical studies reported in the last 2 years demonstrate the importance of several proangiogenic factors in the prognosis of ovarian cancer, suggesting possible new targets for antiangiogenic therapy. The agents that are currently being investigated in phase II and III clinical trials include bevacizumab, erlotinib, sunitinib, sorafenib and vascular endothelial growth factor Trap, and the results of these trials will have significant implications in the future management of ovarian cancer.     

Antiangiogenic agents in combination with chemotherapy in patients with advanced non-small cell lung cancer

Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC.     

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

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

Clinical presentation and management of hand-foot skin reaction associated with sorafenib in combination with cytotoxic chemotherapy: experience in breast cancer

Current combination therapies for advanced breast cancer provide a modest survival benefit but with greater toxicity than with monotherapies. New combinations are needed that improve the efficacy of current treatments and have acceptable tolerability profiles. Recent clinical trials have assessed the efficacy and safety of the multikinase inhibitor sorafenib in combination with common treatments for advanced breast cancer. Sorafenib has both antiangiogenic and antiproliferative activities and is indicated for patients with unresectable hepatocellular and advanced renal cell carcinoma. Generally, sorafenib is associated with manageable, non-life-threatening adverse events. One of the more common adverse events seen with sorafenib is hand-foot skin reaction, a dermatologic toxicity usually localized to the pressure points of the palms and soles. Although hand-foot skin reaction is reversible and not life threatening, it can have a significant impact on a patient's quality of life and may necessitate dose modification. Moreover, sorafenib is being evaluated in combination with breast cancer treatments that are associated with a similar dermatologic toxicity (e.g., capecitabine-induced hand-foot syndrome). This review looks at the use of sorafenib in combination with selected chemotherapies in patients with advanced breast cancer and considers the incidence, prevention, and management of hand-foot skin reaction.     

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

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

Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions.

Angiogenesis is necessary for tumor growth. Drug discovery efforts have identified several potential therapeutic targets on endothelial cells and selective inhibitors capable of slowing tumor growth or producing tumor regression by blocking angiogenesis in in vivo tumor models. Certain antiangiogenic therapeutics increase the activity of cytotoxic anticancer treatments in preclinical models. More than 75 antiangiogenic compounds have entered clinical trials. Most of the early clinical testing was conducted in patients with advanced disease resistant to standard therapies. Several phase III trials have been undertaken to compare the efficacy of standard chemotherapy versus the same in combination with an experimental angiogenesis inhibitor. Preliminary results of the clinical studies suggest that single-agent antiangiogenic therapy is poorly active in advanced tumors. Although some of the results of combination trials are controversial, recent positive outcomes with an antivascular endothelial growth factor antibody combined with chemotherapy as front-line therapy of metastatic colorectal cancer have renewed enthusiasm for this therapeutic strategy. This article presents an overview of experimental and clinical studies of combined therapy with antiangiogenic agents and highlights the challenges related to the appropriate strategies for selection of the patients, study design, and choice of proper end points for preclinical and clinical studies using these agents.     

Targeting angiogenesis in metastatic breast cancer

Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.     

Recent advances in the treatment of renal cell carcinoma and the role of targeted therapies

Immunotherapy confers a small but significant overall survival advantage in metastatic renal cell carcinoma (RCC) but only for the minority of patients, i.e. the 20% with good prognostic features. Recent developments in the molecular biology of renal cell carcinoma have identified multiple pathways associated with the development of this cancer. Several strategies have been investigated targeting these pathways, with significant clinical benefits shown in early studies. New agents including the small molecule targeted inhibitors sunitinib, sorafenib and temsirolimus, and the monoclonal antibody bevacizumab have shown anti-tumour activity in randomised clinical trials and have become the standard of care for most patients. Sunitinib and temsirolimus have shown significant improvements in progression-free survival (sunitinib) and overall survival (temsirolimus) in separate phase III studies in the first-line setting when compared with interferon-alpha. Sorafenib has demonstrated prolonged progression-free survival in a phase III study in comparison with placebo in the second-line setting. More recently two phase III studies have compared bevacizumab and interferon-alpha with interferon-alpha alone. Both studies showed a statistically significant improvement in progression-free survival for the combination arm. Additional studies are needed to optimise the use of these agents by identifying those patients who most benefit and elucidating the best way of delivering them, either in combination or as sequential single agents.     

索拉菲尼联合放疗治疗原发性肝癌的研究进展

 适形放疗是原发性肝癌局部治疗的重要手段之一,但放疗后肝内、肝外转移率较高。索拉菲尼是目前肝癌治疗中惟一被证实有效的药物,可提高晚期肝癌患者的总生存期。索拉菲尼联合放疗,可提高肿瘤细胞辐射敏感性、抑制血管生成、缓解肿瘤乏氧状态、使细胞周期同步化。索拉菲尼联合放疗,已进行了大量生物学研究,Ⅰ、Ⅱ期临床试验也正在开展。