Antiangiogenic treatments and mechanisms of action in renal cell carcinoma

Several angiogenic mechanisms are involved in the pathology of renal cell carcinoma (RCC). Increasing knowledge of angiogenesis and the associated signalling pathways has led to the development of targeted antiangiogenic agents for the treatment of metastatic RCC and the introduction of these agents has significantly improved outcomes for these patients. This article provides an overview of the angiogenic mechanisms implicated in RCC, focusing on the main vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and mammalian target of rapamycin (mTOR) signalling pathways. Targeted antiangiogenic agents for the treatment of mRCC include receptor tyrosine kinase inhibitors (such as sunitinib, sorafenib, pazopanib, axitinib, cediranib and tivozanib), monoclonal antibodies (such as bevacizumab) and mTOR inhibitors (such as temsirolimus and everolimus). In this article, we consider the modes of action of these targeted agents and their differing target receptor profiles and we also evaluate how these correlate with their clinical efficacy and tolerability profiles.     

Antiangiogenic therapy for advanced renal cell carcinoma: Management of treatment-related toxicities

Treatment of metastatic renal cell carcinoma (mRCC) has evolved rapidly over the last two decades as major pathways involved in pathogenesis have been elucidated. These include the vascular endothelial growth factor (VEGF) axis and mammalian target of rapamycin (mTOR). Therapies targeting the VEGF pathway include bevacizumab, sorafenib, sunitinib, pazopanib, and axitinib, whereas temsirolimus and everolimus inhibit the mTOR pathway. All of these novel therapies-VEGF and mTOR inhibitors-are associated with a variety of unique toxicities, some of which may necessitate expert medical management, treatment interruption, or dose reduction. Common adverse events with newer drugs include hypertension, skin reactions, gastrointestinal disturbances, thyroid dysfunction, and fatigue. Skilled management of these toxicities is vital to ensure optimal therapeutic dosing and maximize patient outcomes, including improved survival and quality of life. This review describes and compares the toxicity profiles of novel molecularly targeted agents used in the treatment of mRCC and presents guidance on how best to prevent and manage treatment-related toxicities. Particular attention is given to axitinib, the newest agent to enter the armamentarium. Axitinib is a second-generation receptor tyrosine kinase inhibitor with potent VEGF receptor inhibition that provides durable responses and superior progression-free survival in advanced RCC compared with sorafenib.     

肾细胞癌新辅助靶向治疗的不良反应及其防治

肾细胞癌靶向药物主要有索拉菲尼、舒尼替尼、帕唑帕尼、贝伐珠单抗(联合IFN-α)、替西罗莫司、依维莫司及最近批准的阿西替尼,肾癌术前新辅助治疗和术后辅助治疗极大改善了进展期或转移性肾癌患者的预后。与此同时,靶向治疗药物也会引起手足皮肤反应、高血压、乏力、消化道反应等药物相关性不良反应。因此临床中及时发现并采取有效干预措施,对改善患者生活质量和提高靶向治疗效果尤为重要。     

mTOR-blocking agents in advanced renal cancer: an emerging therapeutic option

Background: The mammalian target of rapamycin (mTOR) pathway inhibition has emerged as one of the main directions for the development of new targeted agents in renal cell carcinoma (RCC). A prominent member in its class of medications, temsirolimus has already been shown to improve overall survival in advanced kidney cancer, when compared with the previous standard, IFN-α. Objective: The aim of this study was to review the most relevant preclinical and clinical data on the mTOR inhibitors, both in clinical use or in current development. Methods: The authors give a comprehensive review of the existing English literature on the role of the mTOR pathway in renal tumorigenesis, as well as a detailed safety and efficacy analysis of older and newer rapamycin analogs. Results/conclusions: Rapamycin derivatives temsirolimus and everolimus have significant clinical activity in patients with advanced-stage RCC. Both parenteral and oral formulations of mTOR inhibitors have shown clinical efficacy and are currently being developed. Combinations of mTOR inhibitors with VEGF/VEGFR-blocking agents are also being studied, in an attempt to further enhance the antineoplastic effect.     

Toxicities of targeted agents in advanced renal cell carcinoma

The targeted therapies available to treat metastatic kidney cancer include vascular endothelial growth factor (VEGF) inhibitors, bevacizumab, sorafenib, sunitinib, pazopanib, and the mTor inhibitors temsirolimus and everolimus. These agents have significantly improved patient outcomes but are associated with toxicities. The most common toxicities seen with the VEGF inhibitors are hypertension, fatigue, and hand- foot syndrome. The mTor inhibitors exhibit a different toxicity profile which includes hyperglycemia and hypertriglyceridemia. Recognition and understanding the mechanism of the toxicities is crucial for optimal patient management.     

Targeting angiogenesis in endometrial cancer - new agents for tailored treatments

Introduction: Endometrial carcinoma represents the most frequent gynecologic tumor in developed countries. The majority of women presents with low-grade tumors but a significant subset of women experience recurrence and do not survive their disease. Patients with stage III/ IV or recurrent endometrial cancer have a poor prognosis. Identification of active and tolerable new targeted agents versus specific molecular targets is a priority objective. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer and in particular endometrial cancer.

Areas covered: In this review, the authors highlight the main angiogenetic molecular pathways and the anti-angiogenic agents in Phase II clinical trials for endometrial cancer treatment. The authors focus on reports from recent years on angiogenesis inhibitors used in endometrial cancer, including anti- vascular endothelial growth factor (VEGF) monoclonal antibodies (bevacizumab and aflibercept), mammalian target of rapamycin inhibitors (mTORi) (everolimus, temsirolimus and ridaforolimus), PI3 K inhibitors (BKM120), tyrosine kinase inhibitors (brivanib, sunitinib, dovitinib and nintedanib) and thalidomide.

Expert opinion: These anti-angiogenic drugs, while used either alone or in combination with chemotherapy, have presented mixed results in treating endometrial cancer patients. Challenges for the future include the identification of new pathways, early identification and overcoming resistance and the use of these molecules in combination with old and new chemotherapeutic and targeted agents.     

Comparative effectiveness of everolimus and axitinib as second targeted therapies for metastatic renal cell carcinoma in the US: a retrospective chart review

Background Second targeted therapies for metastatic renal cell carcinoma (mRCC) include mammalian target of rapamycin inhibitors (mTORis) and tyrosine kinase inhibitors (TKIs). This observational study compares overall survival (OS) and progression-free survival (PFS) of patients treated with everolimus (an mTORi) and axitinib (a TKI) following first TKI, and assesses the impact of type and duration of first TKI on the relative effectiveness of these second targeted therapies.

Methods Retrospective reviews of medical records were conducted by medical oncologists or hematologists/oncologists recruited from a nationwide panel. Included patients with mRCC were required to have discontinued a first TKI (sunitinib, sorafenib, or pazopanib) for medical reasons, and to have initiated everolimus or axitinib as second targeted therapy between February 2012 and January 2013. OS and PFS were compared between patients treated with everolimus vs. axitinib using multivariable Cox proportional hazards regression models. Comparative results were also stratified by type and duration of first TKI.

Results Included patients (n?=?325 for everolimus and n?=?127 for axitinib) had a mean age of 61 years and 31% were female. Sunitinib was the most commonly used first TKI (73%). After adjusting for patient characteristics, no statistically significant differences were observed in OS or PFS between everolimus and axitinib. When stratifying by type and duration of first TKI, there was no statistically significant difference in OS between everolimus and axitinib in all subgroups except for patients with?<6 months on sunitinib or sorafenib as first TKI. No significant difference in PFS was observed in any subgroup.

Limitations Important limitations include potential missing or inaccurate data in medical charts, and confounding due to unobserved factors.

Conclusions In this retrospective chart review, no significant differences were detected in OS or PFS between axitinib and everolimus as second targeted therapy. Longer duration of first TKI was not associated with increased effectiveness of subsequent axitinib compared to everolimus.     

A comprehensive overview of targeted therapy in metastatic renal cell carcinoma

Chemotherapy and immunotherapy failed to deliver decisive results in the systemic treatment of metastatic renal cell carcinoma. Agents representing the current standards operate on members of the RAS signal transduction pathway. Sunitinib (targeting vascular endothelial growth factor), temsirolimus (an inhibitor of the mammalian target of rapamycin - mTOR) and pazopanib (a multi-targeted receptor tyrosine kinase inhibitor) are used in the first line of recurrent disease. A combination of bevacizumab (inhibition of angiogenesis) plus interferon α is also first-line therapy. Second line options include everolimus (another mTOR inhibitor) as well as tyrosine kinase inhibitors for patients who previously received cytokine. We review the results of clinical investigations focusing on survival benefit for these agents. Additionally, trials focusing on new agents, including the kinase inhibitors axitinib, tivozanib, dovitinib and cediranib and monoclonal antibodies including velociximab are also discussed. In addition to published outcomes we also include follow-up and interim results of ongoing clinical trials. In summary, we give a comprehensive overview of current advances in the systemic treatment of metastatic renal cell carcinoma.     

Current and future directions in mammalian target of rapamycin inhibitors development

INTRODUCTION: The mammalian target of the rapamycin (mTOR) signalling pathway has a central role in the regulation of cell growth, survival and angiogenesis and the frequent dysregulation of this pathway in tumor cells makes it a crucial target in the treatment of cancer. Temsirolimus and everolimus are approved for use in metastatic renal cell carcinoma and temsirolimus is also approved for mantle cell lymphoma. All three rapalogs, temsirolimus, everolimus and deforolimus, are currently being evaluated in Phase III studies in several tumors. AREAS COVERED: This paper provides a review of the published literature on the mTOR pathway and related pathway signaling, analogs and novel mTOR inhibitors. The most recent and important data on the mTOR pathway, the role of mTOR inhibitors in cancer treatment and the current status of development of second-generation highly potent and selective mTOR inhibitors are overviewed. EXPERT OPINION: The published data on new mTOR inhibitors are still limited, but the available preclinical results indicate that they have a potent antiproliferative activity against a broad panel of tumor cell lines, have a favorable safety profile, can obtain disease stabilization or even tumor regression and, in some cases, enhance the efficacy of other targeted or standard-of-care anticancer drugs when used in vivo in preclinical studies.     

Targeted therapy of renal cell cancer

Rapid development of treatment strategies for renal cell cancer (RCC) has occurred in recent years. Elucidation of the crucial role of the Von Hippel-Lindau (VHL) tumor suppressor gene in upregulating growth factors associated with angiogenesis has provided new insight into RCC biology and has identified specific targets for novel therapeutic strategies. For almost two decades, cytokine-based immunotherapy has remained a treatment of choice in advanced RCC patients. However, it has provided only modest improvement in clinical outcome and has been associated with severe toxicity. With the advent of novel therapies directly targeting the VEGF molecule or VEGF receptor signal transduction pathway, the clinical outcome in high-risk, advanced RCC has significantly improved. In phase III clinical trials, novel targeted agents - temsirolimus, sorafenib, sunitinib and bevacizumab - significantly prolonged progression-free survival of patients with metastatic RCC and, crucially, temsirolimus also prolonged overall survival in patients with high-risk disease. Despite the obvious clinical efficacy of novel targeted therapies in the treatment of RCC, many unanswered questions still remain; in particular, the efficacy of targeted agents in patients with low-risk RCC, the optimal sequence and combination of therapies for first-, second-, or third-line treatment, and the efficacy of this strategy in adjuvant settings.     

Targeted therapy and hand–foot skin reaction in advanced renal cell carcinoma

Importance of the field: Targeted therapy has significantly prolonged the survival of patients with advanced renal cell carcinoma (RCC). As first-line treatment, sunitinib, temsirolimus and bevacizumab plus IFN-α are demonstrated to prolong progression-free survival and/or overall survival. As second-line treatment, sorafenib was active mainly for patients in whom cytokine therapy failed. Recently, second-line treatment with everolimus has been shown to benefit patients progressing through tyrosine kinase inhibitors. Meanwhile, FDA has just approved pazopanib for the treatment of patients with advanced RCC. Various toxicities were associated with these agents. These toxicities were generally well tolerated. However, a high frequency of severe skin and bone marrow toxicities has been reported in Asian countries.

Areas covered in this review: We have reviewed the literature of current targeted therapeutic agents and hand–foot skin reaction (HFSR) in advanced RCC available in MEDLINE and meeting reports of ASCO, ECCO-ESMO and the 2009 Genitourinary Cancers Symposium.

What the reader will gain: Readers will know of the efficacy and safety, including HFSR, of current targeted therapy.

Take home message: Careful monitoring and appropriate management of the toxicities, especially HFSR, are needed.     

Systemic therapy for metastatic renal cell carcinoma in treatment naïve patients: a risk-based approach

Importance of the field: Kidney cancer is the ninth most common cancer in the USA, with an annual incidence of approximately 55,000 cases per year. Over 13,000 patients are estimated to die from this disease annually. Cloning of the VHL gene, recognition of the associated abnormalities in sporadic clear-cell carcinoma, and its role as a regulator of the hypoxic response, were important milestones in our understanding of renal-cell carcinoma (RCC) biology and the recognition of the vascular endothelial growth factor (VEGF) dependency of RCC. A variety of clinical features, including histologic features, prognostic factors, and patient history of comorbid illness, provide the framework in which the results of recent clinical trials and regulatory approvals of these agents are utilized to develop treatment recommendations for the largest metastatic patient RCC group, the therapy naïve individual.

Areas covered in this review: The rationale for use of VEGF-targeted therapy in advanced RCC patients and the recently developed treatment options for these individuals are reviewed. Regulatory approval of sorafenib for the treatment of metastatic RCC (mRCC), was followed by the approval of sunitinib, temsirolimus, bevacizumab plus interferon (IFNα), everolimus, and – most recently – pazopanib. These licences were granted from late 2005 through late 2009, a very short span of 4 years. In treatment-naïve mRCC patients, sunitinib, sorafenib, pazopanib, bevacizumab + IFNα, and temsirolimus were approved by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMEA). The clinical trials and data supporting these approvals are reviewed.

What will the reader gain: This review examines these developments and provides the reader an overview and understanding of available current systemic therapy options for treatment-naïve mRCC patients.

Take home message: As multiple treatment options are now available for treatment-naïve mRCC patients, an understanding of how to utilize this group of agents is required. The use of various clinical features allows a rational approach to therapy selection. These features include prior treatment status, histologic subtype, and prognostic group. Further refinement of therapy selection is required and will require further biologic information as well as comparative randomized trials.     

Sunitinib in solid tumors

Background: Until recently, few treatments were available for renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST). Several targeted agents inhibiting key pathogenetic pathways have since been developed for RCC (sunitinib, sorafenib, bevacizumab, temsirolimus, everolimus) and GIST (imatinib, sunitinib). Sunitinib is a multi-kinase inhibitor of VEGFR-2, PDGFR (α,β), FLT-3, KIT, CSF-1 and RET. Objective: To summarize the literature regarding the structure, pharmacokinetics, pharmacodynamics, toxicity and current clinical use of sunitinib. Other potential roles for this drug in RCC, GIST and other tumor types will be discussed. Methods: A literature search identified relevant (pre)clinical studies of sunitinib and other relevant agents. Results/conclusions: Sunitinib revolutionized the management of advanced RCC and GIST. With the realization that cross-resistance between targeted agents is incomplete, evolving strategies include sequential treatment, concurrent treatment, and biomarker development. Sunitinib also shows promise in several other tumor types that lack therapeutic options. What remains less clear is its role in tumors that are not heavily dependent on a central pathogenetic pathway, especially if effective cytotoxic therapies exist. Future clinical trials will clarify whether there is a role for sunitinib in these tumors, possibly in combination with cytotoxic agents.     

Exposure-response relationships in patients with metastatic renal cell carcinoma receiving sunitinib: maintaining optimum efficacy in clinical practice

Targeted agents such as sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, have greatly improved the prognosis for patients with metastatic renal cell carcinoma (mRCC). In this review we analyse data from sunitinib preclinical and clinical studies in detail and consider the key implications for the effective use of sunitinib in clinical practice. Sunitinib has shown efficacy and acceptable tolerability in patients with mRCC in phase II and III clinical studies. In a pivotal phase III study in treatment-na?ve patients with mRCC, median progression-free survival for sunitinib-treated patients was double of that with interferon-α (P < 0.001). Median overall survival was 26.4 versus 21.8 months, respectively (P = 0.0510). In preclinical and phase I/II studies, sunitinib inhibits tyrosine kinase inhibitors in a dose-dependent manner, suggesting a correlation between increasing exposure and greater response. A pharmacokinetics/pharmacodynamics meta-analysis investigating the relationship between clinical end points and sunitinib exposure showed that increased sunitinib exposure was associated with a greater probability of objective response, longer time to tumour progression and overall survival, as well as some increased risk of specific adverse events. It is important to consider the relationship between exposure and response to maximize clinical benefit from sunitinib treatment.     

Emerging antiangiogenics for renal cancer

Introduction: Antiangiogenic therapy is considered to be the backbone of treatment strategy in metastatic renal cell carcinoma (mRCC). New, more focused, targeted drugs are emerging, while other targeted drugs oriented toward resistance or alternative mechanisms are under development.

Areas covered: Antiangiogenic agents include two types of agents: the monoclonal antibody, targeting vascular endothelial growth factor (VEGF), bevacizumab and the tyrosine kinase inhibitors (TKIs). Data regarding efficacy and safety of these agents are reported. Differences between the first generation of TKIs, sunitinib, sorafenib, and the new generation, pazopanib, axitinib and tivozanib are also detailed. Most of these agents have been approved in the treatment of kidney cancer in specific settings of the disease.

Expert opinion: The class of antiangiogenic drugs for treatment of mRCC is already relatively full. After ‘me-too' drugs, more targeted drugs against VEGFR have been developed but have to demonstrate a benefit in first-line treatment. Another option for the development is to combine a known drug with an antiangiogenic inhibition profile and at least one additional target involved in resistance to an antiangiogenic or in an alternative pathway. The cost of approach with targeted drugs, including antiangiogenics, has led to a tremendous increase in the cost of care in mRCC.     

Systemic therapies for metastatic renal cell carcinoma in older adults

The introduction of targeted therapies has radically changed the treatment paradigm for metastatic renal cell carcinoma (mRCC). However, multiple clinical dilemmas have emerged. For instance, limited data are available to juxtapose the safety and efficacy profile of targeted therapies between older and younger adults. Herein, pivotal trials of vascular endothelial growth factor (VEGF)- and mammalian target of rapamycin (mTOR)-directed therapies are assessed in the context of their implications in treating older adults with mRCC. In general, subset analyses from these pivotal studies suggest similar efficacy of targeted therapies amongst older adults. Aging is accompanied by a multitude of physiological changes, as well as an increased prevalence of co-morbidities. The age-related toxicity profiles of targeted agents for mRCC are detailed to provide a framework for the risks and benefits of these therapies in older adults. Ultimately, tools such as the Comprehensive Geriatric Assessment (CGA) that account for physiological (as opposed to chronological) age may prove useful in the evaluation and treatment of older adults with mRCC.     

Pazopanib for the treatment of renal cancer

INTRODUCTION: Dramatic advances in the care of patients with advanced renal cell carcinoma (RCC) have occurred over the last 10 years. Insights into the molecular pathogenesis of this disease have elucidated the importance of signaling cascades related to angiogenesis in the management of RCC. Pazopanib is a novel, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3; platelet-derived growth factor receptors (PDGFR)-α and -β; and c-kit tyrosine kinases. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in the class of VEGF signaling pathway inhibitors. AREAS COVERED: This review discusses the scientific rationale for the development of pazopanib, as well as the preclinical and clinical trials that led to the approval of pazopanib for patients with advanced RCC. The most recent information, including data from the 2010 meeting of the American Society of Clinical Oncology and the design of ongoing Phase III trials, is discussed. Finally, an algorithm utilizing level I evidence for the treatment of patients with this disease is proposed. EXPERT OPINION: The treatment of metastatic RCC has changed dramatically over the last 5 years. Six novel agents - sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab (used in combination with interferon), and pazopanib (Votrient) - have been approved for the treatment of metastatic RCC. The clinical data to date clearly place pazopanib among the most active of the targeted therapies.     

Safety of available treatment options for renal cell carcinoma

ABSTRACT

Introduction: For many years, cytokines (high-dose interleukin (IL)-2 and interferon (IFN)) have been the unique available treatment options for metastatic renal cell carcinoma (mRCC) and they provided durable but modest responses at the cost of significant toxicities. To date, targeted therapies have replaced cytokine therapy due to higher response rates and more favorable toxicity profiles. The major classes of targeted therapy for mRCC include tyrosine kinase inhibitors, monoclonal antibody against vascular endothelial grow factors and inhibitors of the mammalian target of rapamycin. Thanks to these new strategies, the prognosis for the mRCC is shifting toward a chronic disease and the new challenges are the adequate treatment of adverse events (AEs) and the care for quality of life, which is crucial. Emerging immunotherapies targeting the programmed death-1 (PD-1) receptor and the programmed death ligand-1 (PD-L1) ligand have shown promising results in both efficacy and safety profiles.

Areas covered: Safety data published on available treatment options for renal cell carcinoma RCC are reviewed.

Expert opinion: Various toxicities are associated with targeted agents; these toxicities are generally well tolerated but careful monitoring and appropriate management are needed to optimize the use of these strategies.     

Sunitinib malate for the treatment of renal cell carcinoma

INTRODUCTION: Over the past decade, a greater understanding into the molecular pathogenesis of renal cell carcinoma (RCC) has led to major advances in treatment options. Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase inhibitor (TKI) that targets a number of receptors, including vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR). Sunitinib was one of the first targeted agents studied in metastatic RCC (mRCC) and is currently used worldwide in the management of mRCC. AREAS COVERED: This drug evaluation addresses the preclinical and clinical development of sunitinib. It provides an in-depth discussion of the Phase II data that led to its approval in mRCC and the subsequent Phase III clinical trial comparing sunitinib to interferon-α. More recent data from the large international expanded access trial, in non-clear cell carcinoma patients, different dosing schedule studies and safety issues are also discussed. Finally, areas for the future use of sunitinib, including in the adjuvant setting, are reviewed. EXPERT OPINION: Since the FDA approved sunitinib for advanced RCC in January 2006, much more has been learned about its efficacy and tolerability. Over the past decade of its clinical use, it has become clear that expertise is required when prescribing sunitinib, in terms of maximizing dose, anticipating and managing side effects, and assessing responses. In the future, a better understanding of sunitinib's role compared with other VEGF TKIs and mTOR inhibitors, and in other roles such as the adjuvant setting or in non-clear cell pathology, will become evident.