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1.  The prospects of pazopanib in advanced renal cell carcinoma 
Therapeutic Advances in Urology  2013;5(5):223-232.
The landscape of treatment for advanced/metastatic renal cell carcinoma (mRCC) has advanced significantly in the last decade and continues to evolve with the approval of new drugs targeting the vascular endothelial growth factor (VEGF) and its receptors and mammalian target of rapamycin (mTOR). Currently available oral VEGF tyrosine kinase inhibitors (TKIs) approved for treatment of mRCC include sorafenib, sunitinib, pazopanib, and axitinib. This review focuses on pazopanib, a multikinase VEGF TKI indicated for patients with treatment-naïve and cytokine-refractory mRCC. This article describes the preclinical and clinical evolution of pazopanib, with an emphasis on its development and role in mRCC. Pivotal trials are discussed that demonstrate the efficacy and safety of pazopanib and its important role in the treatment of patients with mRCC in comparison to other available treatment options. The clinical path of pazopanib continues to develop further, with several ongoing studies exploring its role in neoadjuvant and adjuvant RCC. Furthermore, its potential role in sequential and combination studies with other VEGFR and non-VEGFR targeted agents is discussed. Overall, pazopanib is a unique VEGF TKI, with a different and more favorable safety profile compared with other members of the VEGF TKI family and represents an attractive alternative for patients with mRCC.
doi:10.1177/1756287213495099
PMCID: PMC3763778  PMID: 24082917
kidney cancer; pazopanib; renal cell carcinoma; targeted therapy; tyrosine kinase inhibitors; vascular endothelial growth factor
2.  Targeted therapy for metastatic renal cell carcinoma: current treatment and future directions 
An understanding of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways has greatly changed the way metastatic renal cell carcinoma (RCC) is treated. Based on available phase III randomized trials, anti-VEGF agents such as sunitinib, sorafenib, bevacizumab-based therapy, and mTOR-targeted agents such as temsirolimus and everolimus have been used in the treatment armamentarium for this disease. Now that agents directed against these pathways have largely replaced immunotherapy as the standard of care, new questions have emerged and are the subject of ongoing clinical trials. The development of new targeted therapies including axitinib, pazopanib, cediranib, volociximab, tivozanib (AV-951), BAY 73-4506, and c-met inhibitors such as GSK1363089 and ARQ197 may potentially expand the list of treatment options. Sequential and combination targeted therapies are currently under investigation in advanced disease as are adjuvant and neo-adjuvant approaches around nephrectomy.
doi:10.1177/1758834009352498
PMCID: PMC3126007  PMID: 21789125
adjuvant; combination therapy; mammalian target of rapamycin; neo-adjuvant; nonclear cell histologies; renal cell carcinoma; vascular endothelial growth factor
3.  Review of US Comparative Economic Evidence for Treatment of Metastatic Renal Cell Carcinoma after Failure of First-Line VEGF Inhibitor Therapy 
American Health & Drug Benefits  2013;6(5):275-286.
Background
In 2006, the economic burden of metastatic renal cell carcinoma (mRCC) was estimated to be up to $1.6 billion worldwide and has since grown annually. With the continuing increase of the economic burden of this disease in the United States, there is a growing need for economic analyses to guide treatment and policy decisions for this patient population.
Objective
To evaluate available comparative economic data on targeted therapies for patients with mRCC who have failed first-line targeted therapies.
Method
A broad and comprehensive literature review was conducted of US-based studies between January 1, 2005, and February 11, 2013, evaluating comparative economic evidence for targeted agents that are used as second-line therapy or beyond. Based on the specific search parameters that focused on cost-effectiveness and economic comparisons between vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFr) inhibitors and mammalian target of rapamycin (mTOR) inhibitors, only 7 relevant, US-based economic evaluations were found appropriate for inclusion in the analysis. All authors, who are experts in the health economics and outcomes research field, reviewed the search results. Studies of interest were those with a targeted agent, VEGF/VEGFr or mTOR inhibitor, in at least 1 study arm.
Discussion
As a group, targeted therapies were found to be cost-effective options in treating patients with refractory mRCC in the United States. Oral therapies showed an economic advantage over intravenous agents, presumably because oral therapies have a lower impact on outpatient resources. Based on 3 studies, everolimus has been shown to have an economic advantage over temsirolimus and to be cost-effective compared with sorafenib. No economic comparison between everolimus and axitinib, the only 2 drugs with a National Comprehensive Cancer Network category 1 recommendation for use after the failure of VEGFr tyrosine kinase inhibitors, is available.
Conclusion
The limited and heterogeneous sum of the currently available economic evidence does not allow firm conclusions to be drawn about the most cost-effective targeted treatment option in the second-line setting and beyond in patients with mRCC. It is hoped that ongoing head-to-head therapeutic trials and biomarker studies will help improve the economic efficiency of these expensive agents.
PMCID: PMC4031714  PMID: 24991363
4.  Axitinib for the Management of Metastatic Renal Cell Carcinoma 
Drugs in R&d  2012;11(2):113-126.
In recent years, targeted agents have changed the treatment landscape for patients with advanced renal cell carcinoma (RCC), greatly improving treatment outcomes. Several targeted agents are now licensed for the treatment of metastatic RCC (mRCC), and a number of new agents are under investigation. Axitinib, a small molecule indazole derivative is an oral, potent multitargeted tyrosine kinase receptor inhibitor, which selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 at subnanomolar concentrations, in vitro. In various nonclinical models, axitinib has demonstrated in vivo target modulation and antiangiogenesis. In pharmacokinetic studies, axitinib administered orally with food at the proposed regimen of 5mg twice daily continuous daily dosing, is rapidly absorbed, reaching peak concentrations within 2–6 hours. Axitinib is metabolized primarily in the liver via the cytochrome P450 (CYP) system with less than 1% of the administered drug passing unchanged in the urine. The pharmacokinetics of axitinib do not appear to be altered by coadministered chemotherapies, and antacids do not have a clinically significant effect. However, coadministration with CYP3A4 and 1A2 inducers is contraindicated. In addition, proton pump inhibitors reduce the rate of axitinib absorption. Increased axitinib exposure is associated with higher efficacy indicated by decreased tumor perfusion and volume. In three phase II clinical trials in patients with advancedRCCpreviously treated with cytokines, chemotherapy or targeted agents, axitinib has demonstrated antitumor activity with a favorable noncumulative toxicity profile. In one study of Western patients with cytokine-refractory mRCC, an objective response rate (ORR) of 44.2% (95% CI 30.5, 58.7) was achieved. The median time to progression was 15.7 months (95%CI 8.4, 23.4) and the median overall survival (OS) was 29.9 months (95%CI 20.3, not estimable). In the second study of patients with sorafenib-refractory mRCC, ORR was 22.6% (95% CI 12.9, 35.0). The median progression-free survival (PFS) was 7.4 months (95% CI 6.7, 11.0) and a median OS of 13.6 months (95% CI 8.4, 18.8) was achieved. Results from the third study in Japanese patients with cytokine-refractory mRCC reported an ORR of 55% and median PFS of 12.9 months (95% CI 9.8, 15.6).
In the three studies, themost common adverse events reported were fatigue, hypertension, hand-foot syndrome (HFS), and gastrointestinal toxicity, which were generally manageable with standard medical intervention. Of note, the incidence of HFS and proteinuria in the Japanese study was higher than that reported in the Western study in cytokine-refractory mRCC patients.
An observed association between diastolic blood pressure ≥90 mmHg and increased efficacy suggests potential use as a prognostic biomarker. However, this requires further investigation. Two randomized phase III clinical trials are ongoing to determine the efficacy of axitinib in patients with mRCC in the first- and second-line setting. These results will help to determine the place of axitinib in the mRCC treatment algorithm.
doi:10.2165/11591240-000000000-00000
PMCID: PMC3585900  PMID: 21679004
5.  Axitinib for the Management of Metastatic Renal Cell Carcinoma 
Drugs in R&D  2012;11(2):113-126.
In recent years, targeted agents have changed the treatment landscape for patients with advanced renal cell carcinoma (RCC), greatly improving treatment outcomes. Several targeted agents are now licensed for the treatment of metastatic RCC (mRCC), and a number of new agents are under investigation. Axitinib, a small molecule indazole derivative is an oral, potent multitargeted tyrosine kinase receptor inhibitor, which selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 at subnanomolar concentrations, in vitro. In various nonclinical models, axitinib has demonstrated in vivo target modulation and antiangiogenesis. In pharmacokinetic studies, axitinib administered orally with food at the proposed regimen of 5mg twice daily continuous daily dosing, is rapidly absorbed, reaching peak concentrations within 2–6 hours. Axitinib is metabolized primarily in the liver via the cytochrome P450 (CYP) system with less than 1% of the administered drug passing unchanged in the urine. The pharmacokinetics of axitinib do not appear to be altered by coadministered chemotherapies, and antacids do not have a clinically significant effect. However, coadministration with CYP3A4 and 1A2 inducers is contraindicated. In addition, proton pump inhibitors reduce the rate of axitinib absorption. Increased axitinib exposure is associated with higher efficacy indicated by decreased tumor perfusion and volume. In three phase II clinical trials in patients with advancedRCCpreviously treated with cytokines, chemotherapy or targeted agents, axitinib has demonstrated antitumor activity with a favorable noncumulative toxicity profile. In one study of Western patients with cytokine-refractory mRCC, an objective response rate (ORR) of 44.2% (95% CI 30.5, 58.7) was achieved. The median time to progression was 15.7 months (95%CI 8.4, 23.4) and the median overall survival (OS) was 29.9 months (95%CI 20.3, not estimable). In the second study of patients with sorafenib-refractory mRCC, ORR was 22.6% (95% CI 12.9, 35.0). The median progression-free survival (PFS) was 7.4 months (95% CI 6.7, 11.0) and a median OS of 13.6 months (95% CI 8.4, 18.8) was achieved. Results from the third study in Japanese patients with cytokine-refractory mRCC reported an ORR of 55% and median PFS of 12.9 months (95% CI 9.8, 15.6).
In the three studies, themost common adverse events reported were fatigue, hypertension, hand-foot syndrome (HFS), and gastrointestinal toxicity, which were generally manageable with standard medical intervention. Of note, the incidence of HFS and proteinuria in the Japanese study was higher than that reported in the Western study in cytokine-refractory mRCC patients.
An observed association between diastolic blood pressure ≥90 mmHg and increased efficacy suggests potential use as a prognostic biomarker. However, this requires further investigation. Two randomized phase III clinical trials are ongoing to determine the efficacy of axitinib in patients with mRCC in the first- and second-line setting. These results will help to determine the place of axitinib in the mRCC treatment algorithm.
doi:10.2165/11591240-000000000-00000
PMCID: PMC3585900  PMID: 21679004
6.  Optimal first-line and second-line treatments for metastatic renal cell carcinoma: current evidence 
Since 2005, an abundance of targeted agents has been approved for the treatment of metastatic renal cell carcinoma (mRCC), without any specification as to what may be the most optimal first-line and second-line sequence. Hence, our objective was to critically examine the evidence supporting the use of first-line and second-line agents in the management of mRCC. Our review suggests that in first line, sunitinib and pazopanib represent treatment options for patients with favorable or intermediate-risk features and clear cell histology. Unfortunately, the Phase III trial cannot conclusively prove the noninferiority of pazopanib relative to sunitinib. Hence, the use of sunitinib as first-line standard of care remains justified. Pazopanib represents an option for specific patients in whom sunitinib might not be tolerated. In patients with poor-risk features, temsirolimus represents the only option supported with level 1 evidence. Less optimal alternatives include sunitinib and bevacizumab combined with interferon, based on the minimal inclusion of poor-risk patients in pivotal Phase III studies of these two molecules. In patients with non-clear cell mRCC, the use of temsirolimus is supported by Phase III data, unlike for any other molecule. In second line, the options consist of everolimus and axitinib. However, the axitinib data are substantially more robust given the inclusion of more patients considered as true second-line, and validly justify the choice of axitinib over everolimus. Nonetheless, the Phase III trial of everolimus may be considered as level 1 evidence for use as third-line or subsequent lines of therapy.
doi:10.2147/IJNRD.S48496
PMCID: PMC4219683  PMID: 25378943
targeted therapy; metastatic; renal cell carcinoma; clear cell; sequential therapy
7.  Current Status of Targeted Therapy for Advanced Renal Cell Carcinoma 
Korean Journal of Urology  2012;53(4):217-228.
The treatment of metastatic renal cell carcinoma (mRCC) has recently evolved from being predominantly cytokine-based treatment to the use of targeted agents, which include sorafenib, sunitinib, bevacizumab (plus interferon alpha [IFN-α]), temsirolimus, everolimus, pazopanib, and most recently, axitinib. Improved understanding of the molecular pathways implicated in the pathogenesis of RCC has led to the development of specific targeted therapies for treating the disease. In Korea, it has been 5 years since targeted therapy became available for mRCC. Thus, we now have broader and better therapeutic options at hand, leading to a significantly improved prognosis for patients with mRCC. However, the treatment of mRCC remains a challenge and a major health problem. Many questions remain on the efficacy of combination treatments and on the best methods for achieving complete remission. Additional studies are needed to optimize the use of these agents by identifying those patients who would most benefit and by elucidating the best means of delivering these agents, either in combination or as sequential single agents. Furthermore, numerous ongoing research activities aim at improving the benefits of the new compounds in the metastatic situation or their application in the early phase of the disease. This review introduces what is currently known regarding the fundamental biology that underlies clear cell RCC, summarizes the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in pivotal clinical trials, and outlines future research directions.
doi:10.4111/kju.2012.53.4.217
PMCID: PMC3332131  PMID: 22536463
Molecular targeted therapy; mTOR protein; Renal cell carcinoma; Vascular endothelial growth factor A
8.  Future directions of mammalian target of rapamycin (mTOR) inhibitor therapy in renal cell carcinoma 
Targeted Oncology  2011;6(1):5-16.
With an explosion of available treatments for metastatic renal cell carcinoma (mRCC) in recent years, it is important to recognize that approved targeted therapies fall broadly into only two mechanistic categories. The first category, vascular endothelial growth factor (VEGF)-directed therapies, includes sunitinib, pazopanib, sorafenib and bevacizumab. The second category includes inhibitors of the mammalian target of rapamycin (mTOR), namely everolimus and temsirolimus. A pivotal trial of ever-olimus supports use of the agent in patients with mRCC refractory to VEGF- tyrosine kinase inhibitors (TKI) therapy, while pivotal data for temsirolimus supports use in poor-prognosis patients as first-line therapy. Multiple reviews exist to delineate the laboratory and clinical development of mTOR inhibitors. This paper will outline the future applications of these therapies. It will explore ongoing trials evaluating combinations of mTOR inhibitors with other targeted therapies, along with sequencing strategies and biomarker discovery efforts. The application of mTOR inhibitors in unique populations is also described.
doi:10.1007/s11523-011-0172-y
PMCID: PMC3253822  PMID: 21484496
mTOR; Everolimus; Temsirolimus; Deferolimus; INTORACT; TORAVA; BeST; Biomarkers; Clinical trials
9.  Progress of Molecular Targeted Therapies for Advanced Renal Cell Carcinoma 
BioMed Research International  2013;2013:419176.
Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis. VEGF expression in metastatic renal cell carcinoma (mRCC) is mostly regulated by hypoxia, predominantly via the hypoxia-induced factor (HIF)/Von Hippel-Lindau (VHL) pathway. Advances in our knowledge of VEGF role in tumor angiogenesis, growth, and progression have permitted development of new approaches for the treatment of mRCC, including several agents targeting VEGF and VEGF receptors: tyrosine kinase pathway, serine/threonine kinases, α5β1-integrin, deacetylase, CD70, mammalian target of rapamycin (mTOR), AKT, and phosphatidylinositol 3′-kinase (PI3K). Starting from sorafenib and sunitinib, several targeted therapies have been approved for mRCC treatment, with a long list of agents in course of evaluation, such as tivozanib, cediranib, and VEGF-Trap. Here we illustrate the main steps of tumor angiogenesis process, defining the pertinent therapeutic targets and the efficacy and toxicity profiles of these new promising agents.
doi:10.1155/2013/419176
PMCID: PMC3777192  PMID: 24093097
10.  Treatment Options in Metastatic Renal Cell Carcinoma: Focus on mTOR Inhibitors 
The agents currently approved for use in metastatic renal cell carcinoma (mRCC) can be divided broadly into two categories: (1) vascular endothelial growth factor receptor (VEGFR)-directed therapies or (2) inhibitors of the mammalian target of rapamycin (mTOR). The latter category includes everolimus and temsirolimus, both approved for distinct indications in mRCC. Everolimus gained its approval on the basis of phase III data showing a benefit in progression-free survival relative to placebo in patients previously treated with sunitinib and/or sorafenib. In contrast, temsirolimus was approved on the basis of a phase III trial in treatment-naïve patients with poor-risk mRCC, demonstrating an improvement in overall survival relative to interferon-alfa. While these pivotal trials have created unique positions for everolimus and temsirolimus in current clinical algorithms, the role of mTOR inhibitors in mRCC is being steadily revised and expanded through ongoing trials testing novel sequences and combinations. The clinical development of mTOR inhibitors is outlined herein.
PMCID: PMC2902205  PMID: 20711245
metastatic renal cell carcinoma; mRCC; mTOR inhibitors
11.  Bevacizumab Demonstrates Prolonged Disease Stabilization in Patients with Heavily Pretreated Metastatic Renal Cell Carcinoma: A Case Series and Review of the Literature 
Advances in Urology  2010;2010:687043.
There are now a variety of therapies approved for the treatment of metastatic renal cell carcinoma (RCC). These include the immunotherapeutics, alfa-interferon, and interleukin-2, and agents that target the vascular endothelial growth factor receptor (VEGFR) via its tyrosine kinase, such as sorafenib, sunitinib, and pazopanib, or the mammalian target of rapamycin (mTOR), such as temsirolimus and everolimus. Bevacizumab, a monoclonal antibody directed against the ligand, VEGF, has shown activity against RCC as a single agent in patients who had failed prior cytokine therapy and as first line therapy in combination with interferon. The activity of bevacizumab in patients who had received and failed prior therapy has not been described. We report our experience in 4 patients with metastatic RCC who had failed prior cytokine, TKI, and mTOR inhibitors who were treated with bevacizumab as single agent therapy. These heavily pretreated patients sustained very prolonged periods of stable disease (median of 12 months) with very little toxicity and excellent quality of life. The activity of this agent in patients who had failed prior therapies directed against the VEGFR and mTOR suggests that therapy targeting the ligand, VEGF, is still a viable approach in these patients and deserves further study.
doi:10.1155/2010/687043
PMCID: PMC2913531  PMID: 20721275
12.  Targeted therapy in renal cancer 
Renal cell cancer (RCC) has an increasing incidence internationally and is a disease for which there have been limited therapeutic options until recently. The last decade has seen a vastly improved understanding of the biological and clinical factors that predict the outcome of this disease. We now understand some of the different molecular underpinnings of renal clear cell carcinoma by mutation or silencing of the von Hippel Lindau (VHL) gene and subsequent deregulated proliferation and angiogenesis. Survival in advanced disease is predicted by factors (performance status, anemia, hypercalcemia, and serum lactate dehydrogenase, time from diagnosis to recurrence) incorporated into the Memorial Sloan Kettering Cancer Center (MSKCC) criteria (also referred to as ‘Motzer’ criteria). These criteria allow classification of patients with RCC into good, intermediate and poor risk categories with median overall survivals of 22 months, 12 months and 5.4 months, respectively. Predicated upon these advances, six new targeted drugs (sorafenib, sunitinib, temsirolimus, everolimus, bevacizumab and pazopanib) have been tested in well-designed phase III trials, selected or stratified for MSKCC risk criteria, with positive results. All of these new drugs act at least in part through vascular endothelial growth factor (VEGF) mediated pathways with other potential therapeutic impact on platelet-derived growth factor (PDGF), raf kinase and mammalian target of rapamycin (mTOR) pathways. Importantly, data from each of these trials show a consistent doubling of progression-free survival (PFS) over prior standard of care treatments. In addition, sorafenib, sunitinib and temsirolimus, have demonstrated significant overall survival (OS) benefits as well; further follow-up is required to determine whether the disease control exhibited by everolimus and pazopanib will translate into a survival advantage. These drugs are generally well tolerated, as demonstrated by quality-of-life improvement in clinical trials, and result in clinical benefit for in excess of 70% of patients treated. They have challenged the traditional outcomes of clinical trial design by achieving their benefits with relatively few radiographic responses, but high rates of disease stability. The unique side-effect profile coupled with the chronicity of therapy requires increased vigilance to maximize exposure to the drugs while maintaining quality of life and minimizing toxicity. This review focuses on the background, clinical development and practical use of these new drugs in RCC.
doi:10.1177/1758834009349119
PMCID: PMC3125999  PMID: 21789121
renal cell carcinoma; bevacizumab; everolimus; sorafenib; sunitinib; temsirolimus
13.  Targeted therapies for renal cell carcinoma in Chinese patients: focus on everolimus 
OncoTargets and therapy  2015;8:313-321.
Renal cell carcinoma (RCC) is the most common type of cancer arising from the kidney, with a male to female ratio of 2:1. The incidence of RCC is rising. In males, it was the seventh most common cancer in the People’s Republic of China in 2012. RCC is resistant to radiotherapy and chemotherapy, but approximately 20% of patients with advanced RCC respond to immunotherapy. Novel therapies targeting angiogenesis and signaling pathways have been proven to be effective for advanced or metastatic RCC in Western countries. Due to the heterogeneity of RCC between races, it is necessary to have an overview of targeted therapies, especially everolimus, for patients with advanced RCC in the People’s Republic of China. Three targeted therapeutic agents have been approved in Mainland China for the treatment of patients with advanced RCC, ie, two tyrosine kinase inhibitors (sorafenib and sunitinib) and one mammalian target of rapamycin (mTOR) inhibitor (everolimus). Compared with Western patients with advanced or metastatic RCC, Chinese patients with the same disease respond better to sorafenib and sunitinib as first-line targeted therapy, but sunitinib has a relatively higher risk of toxicity. Everolimus, an mTOR inhibitor that can be administered orally, is well tolerated and acceptable to Chinese patients. Everolimus has competitive advantages as second-line targeted treatment for Chinese patients with advanced RCC who are resistant to first-line tyrosine kinase inhibitors. Despite a lack of noninferiority when compared with sunitinib as first-line therapy, the sunitinib-everolimus paradigm is still recommended as standard therapy for patients with advanced RCC. Although most studies of targeted therapies for advanced RCC have obvious limitations, such as small sample size and retrospective design, up-to-date evidence indicates that everolimus would be an ideal agent as second-line targeted treatment for advanced or metastatic RCC in the People’s Republic of China.
doi:10.2147/OTT.S64660
PMCID: PMC4321650
target therapy; renal cell carcinoma; everolimus; People’s Republic of China
14.  Phase I trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma 
Cancer  2011;118(7):1868-1876.
Background
Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor (TKI) targeting VEGF are standard agents in the management of metastatic RCC.
Methods
Sequential cohorts of 3 to 6 patients with advanced RCC received dose escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on / 2 weeks off) with everolimus (2.5–5 mg daily or 20–30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine MTD. Pharmacokinetic profiles were obtained.
Results
20 patients (13 clear cell and 7 non-clear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the 2nd cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1–28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, 3 had non-clear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed.
Conclusions
The combination everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in non-clear cell and clear cell RCC.
doi:10.1002/cncr.26429
PMCID: PMC3609026  PMID: 21898375
renal cell carcinoma; everolimus; sunitinib; targeted therapy; combination drug therapy
15.  Pharmacotherapy Options in Advanced Renal Cell Carcinoma: What Role for Pazopanib? 
Over the last 6 years, the treatment of metastatic renal cell carcinoma (mRCC) has undergone dramatic changes. A better understanding of the pathogenesis and tumor biology of sporadic renal cell carcinoma has led to the approval of 6 drug regimens: 3 oral multi-targeted tyrosine-kinase inhibitors (sorafenib, sunitinib, and pazopanib), 2 inhibitors of the mammalian target of rapamycin (temsirolimus and everolimus), and 1 monoclonal antibody against the vascular endothelial growth factor (bevacizumab). Pazopanib, a multi-targeted tyrosine kinase inhibitor that targets VEGFR-1, -2, and-3; PDGFR-α and PDGFR-β, and c-Kit, was approved for the treatment of mRCC in October 2009, several years after the other drugs in its class. The efficacy and safety of pazopanib in Phase I, II, and III trials will be examined and its role in mRCC treatment will be described. Future studies that may clarify pazopanib’s role in mRCC will be discussed. Based on pazopanib’s demonstrated efficacy in treatment-naïve and cytokine-refractory patients, along with a seemingly favorable toxicity profile compared with other multi-targeted tyrosine-kinase inhibitors, pazopanib may have a unique niche in the armamentarium of treatment options for mRCC. Results from ongoing studies are awaited to confirm pazopanib’s favorable efficacy-toxicity ratio, especially in comparison with the previous first-line standard-of-care, sunitinib.
doi:10.4137/CMO.S6087
PMCID: PMC3235998  PMID: 22174596
pazopanib; GW786034; VEGFR; TKI; renal cell carcinoma
16.  Safety and efficacy of everolimus in Chinese patients with metastatic renal cell carcinoma resistant to vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy: an open-label phase 1b study 
BMC Cancer  2013;13:136.
Background
In China, there are currently no approved therapies for the treatment of metastatic renal cell carcinoma (mRCC) following progression with vascular endothelial growth factor (VEGF)-targeted agents. In the phase 3 RECORD-1 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus afforded clinical benefit with good tolerability in Western patients with mRCC whose disease had progressed despite VEGF receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. This phase 1b study was designed to further evaluate the safety and efficacy of everolimus in VEGFr-TKI-refractory Chinese patients with mRCC.
Methods
An open-label, multicenter phase 1b study enrolled Chinese patients with mRCC who were intolerant to, or progressed on, previous VEGFr-TKI therapy (N = 64). Patients received everolimus 10 mg daily until objective tumor progression (according to RECIST, version 1.0), unacceptable toxicity, death, or study discontinuation for any other reason. The final data analysis cut-off date was November 30, 2011.
Results
A total of 64 patients were included in the study. Median age was 52 years (range, 19–75 years) and 69% of patients were male. Median duration of everolimus therapy was 4.1 months (range, 0.0-16.1 months). Expected known class-effect toxicities related to mTOR inhibitor therapy were observed, including anemia (64%), hypertriglyceridemia (55%), mouth ulceration (53%), hyperglycemia (52%), hypercholesterolemia (50%), and pulmonary events (31%). Common grade 3/4 adverse events were anemia (20%), hyperglycemia (13%), increased gamma-glutamyltransferase (11%), hyponatremia (8%), dyspnea (8%), hypertriglyceridemia (6%), and lymphopenia (6%). Median PFS was 6.9 months (95% CI, 3.7-12.5 months) and the overall tumor response rate was 5% (95% CI, 1-13%). The majority of patients (61%) had stable disease as their best overall tumor response.
Conclusions
Safety and efficacy results were comparable to those of the RECORD-1 trial. Everolimus is generally well tolerated and provides clinical benefit to Chinese patients with anti-VEGF-refractory mRCC.
Trial registration
clinicaltrials.gov, NCT01152801
doi:10.1186/1471-2407-13-136
PMCID: PMC3626915  PMID: 23514360
Asian; Everolimus; mTOR inhibitor; Renal cell cancer; Sunitinib; Sorafenib
17.  Indirect comparisons of efficacy and safety between seven newer targeted agents for metastatic renal cell carcinoma: A network meta-analysis of randomised clinical trials 
Molecular and Clinical Oncology  2014;2(5):858-864.
This network meta-analysis aimed to compare the clinical efficacy and safety among 7 newer targeted agents for the treatment of metastatic renal cell carcinoma (mRCC). All randomised clinical trials (RCTs) of targeted therapeutic drugs for mRCC were included. The study selection, data extraction and quality assessment were performed independently by two reviewers. The analysis evaluated efficacy outcomes [improvement in the median progression-free survival (PFS)] and safety outcomes (number of withdrawals due to adverse events). The network analysis included direct and indirect analyses. The quality of the selected studies was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) method. We identified 7 articles eligible for inclusion in the study. The direct comparison of the targeted agents indicated better efficacy in terms of longer PFS, but worse safety (more withdrawals due to adverse events). The indirect analysis demonstrated that axitinib was significantly more effective compared to panzopanib; sunitinib was superior to sorafenib and temsirolimus regarding efficacy outcome, without any statistically significant difference in the safety outcome. The results of the quality assessment indicated moderate scores using the GRADE method. In conclusion, the result of this network analysis suggested that sunitinib and axitinib may be more clinically efficient and axitinib is associated with a lower risk of adverse events compared to sorafenib, pazopanib and temsirolimus.
doi:10.3892/mco.2014.323
PMCID: PMC4106731  PMID: 25054058
mixed treatment comparisons; targeted therapy; progression-free survival; hazard ratio; serious adverse event; metastatic renal cell carcinoma; indirect treatment comparisons; GPU-Enabled Many-Task Computing
18.  Systemic therapy for advanced renal cell carcinoma 
Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and is refractory to cytotoxic chemotherapy – immunotherapy has until recently been the standard of care for advanced disease. Randomised trials reported in the last 5 years have demonstrated that a number of agents including the monoclonal antibody, bevacizumab, and the kinase inhibitors – sorafenib sunitinib, temsirolimus and everolimus – are active in advanced RCC. Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus and everolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively. In the second-line setting, everolimus has shown benefit over placebo in patients who progress following treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demonstrated efficacy in comparison with placebo in patients with immunotherapy-refractory disease. We review here recent clinical trial data and discuss future developments in the systemic treatment of RCC including combination and sequential therapy, adjuvant therapy, the role of biomarkers and the prospects for the development of rational mechanism-directed therapy in this disease.
doi:10.1177/1758834009338430
PMCID: PMC3125990  PMID: 21789110
renal cell carcinoma; bevacizumab; sorafenib; sunitinib; temsirolimus; everolimus
19.  Critical appraisal of pazopanib as treatment for patients with advanced metastatic renal cell carcinoma 
The management of renal cell carcinoma (RCC) has undergone significant changes during the past 10 years, with the treatment of metastatic RCC undergoing the most radical changes. These developments reflect an enhanced understanding of this tumor’s underlying biology, which was then translated into the development of a new treatment paradigm. Current therapeutic approaches for the management of patients with metastatic RCC utilize knowledge of histology, molecular abnormalities, clinical prognostic factors, the natural history of this malignancy, and the treatment efficacy and toxicity of available agents. The treatment options available for patients with metastatic RCC have changed dramatically over the past 6 years. Interferon-α and interleukin-2 were the previous mainstays of therapy, but since December 2005, six new agents have been approved in the US for the treatment of advanced RCC. Three are multi-targeted tyrosine kinase inhibitors (TKI) including sunitinib, sorafenib, and pazopanib, two target the mammalian target of rapamycin (temsirolimus and everolimus), and one is a humanized monoclonal antibody (bevacizumab in combination with interferon-α). The current review focuses on the newest TKI available to treat patients with metastatic RCC, pazopanib. The development of this agent both preclinically and clinically is reviewed. The efficacy and safety data from the pivotal clinical trials are discussed, and the potential role of pazopanib in the treatment of patients with metastatic RCC in comparison to other treatment alternatives is critically appraised. This agent has a favorable overall risk benefit, and the available data demonstrate efficacy in patients with metastatic RCC who are either treatment-naïve or cytokine refractory. It therefore represents another alternative for treatment of metastatic RCC patients.
doi:10.2147/CMR.S15557
PMCID: PMC3173017  PMID: 21931501
renal cell carcinoma; metastatic; pazopanib
20.  Everolimus – a new approach in the treatment of renal cell carcinoma 
With the increasing understanding of the biology of the disease and the development of targeted therapy, there has been a paradigm shift in the treatment of clear cell metastatic renal cell carcinoma (mRCC). Traditionally patients with metastatic RCC have been treated with immunotherapy which has limited efficacy. The multikinase inhibitors sunitinib, sorafenib and pazopanib, the VEGF antibody bevacizumab in combination with interferon and the mTOR inhibitor temsirolimus have all been shown to prolong progression-free survival in phase III studies. Here we review another mTOR inhibitor, everolimus (Afinitor®; Novartis, USA) which was approved in March 2009 by the US FDA for treatment of targeted-therapy refractory metastatic renal cell cancer. The phase III study of everolimus (the RECORD study) was terminated early after a significant difference in efficacy was noted in the treatment arm with everolimus (progression-free survival of 4.0 months in patients on the treatment arm vs 1.9 months in the placebo arm). The most common adverse events were stomatitis, pneumonitis, fatigue and infections. We review Phase I–III data with a particular emphasis on safety data and patient focused outcomes.
PMCID: PMC3004583  PMID: 21188097
metastatic renal cell carcinoma; targeted therapy; mTOR; everolimus
21.  Safety and efficacy of targeted agents in metastatic kidney cancer patients with renal dysfunction 
Anti-cancer drugs  2011;22(8):794-800.
Background:
Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma(mRCC). Sunitinib and M-TOR inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, while the metabolism of bevacizumab is unclear. There are limited data on the toxicity profile and efficacy of these agents in patients with renal impairment(RI). This is clinically relevant especially since about one third of mRCC patients have renal dysfunction.
Methods:
The primary objective was to assess the safety and efficacy of targeted agents in mRCC patients with RI. Medical records of patients with mRCC at Wayne State University started on sunitinib, temsirolimus, everolimus or bevacizumab were reviewed. Patients with a calculated creatinine clearance(CrCl) of ≤60ml/min were deemed to have RI. Data on safety and efficacy of MTA therapy were collected and analyzed with respect to renal function.
Results:
RI was observed in 33% of our mRCC patients. The incidence of toxicities, responses, time to progression(TTP), and overall survival(OS) were not significantly different in patients with RI compared to patients with normal renal function. Patients with RI had larger median increases in blood pressure with sunitinib and bevacizumab, increased incidence of thyroid dysfunction with sunitinib, and increased incidence of rash and dose interruptions with m-TOR inhibitors, than did patients with normal renal function.
Conclusions:
RI was commonly observed in our mRCC patients. MTAs are well tolerated and efficacy appears to be maintained in patients with RI. Vigilant monitoring of hypertension would be recommended for pts receiving sunitinib and bevacizumab.
doi:10.1097/CAD.0b013e328346af0d
PMCID: PMC3149855  PMID: 21799472
renal dysfunction; kidney cancer; sunitinib; temsirolimus; bevacizumab; everolimus
22.  Treatment-Associated Adverse Event Management in the Advanced Renal Cell Carcinoma Patient Treated with Targeted Therapies 
The Oncologist  2011;16(Suppl 2):32-44.
The common toxicities observed during clinical trials of targeted therapies for advanced renal cell carcinoma as well as specific reported side effects are discussed, and recommended strategies to anticipate the occurrence of key adverse events, minimize the risk for increasing adverse event severity, and manage toxicities to help optimize treatment outcomes in patients with advanced renal cell carcinoma are highlighted.
Targeted therapy for advanced renal cell carcinoma (RCC) has recently expanded the available treatment options for patients with these malignancies. The rapid introduction of novel treatment options into clinical practice within a relatively short time frame has created some new challenges pertaining to adverse event (AE) management in patients with advanced RCC. Accumulating safety data from the pivotal phase III clinical trials of the anti–vascular endothelial growth factor (VEGF) antibody bevacizumab plus interferon, VEGF receptor tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), and mammalian target of rapamycin inhibitors (temsirolimus and everolimus) have served to characterize the toxicity profiles of these novel agents. Overall, it is evident that RCC-directed targeted therapy differs from immunotherapy and cytotoxic chemotherapy in terms of a number of unique nonhematologic AEs (some of which have not been traditionally encountered in oncology practice) and that there are distinctions within and across the various classes of agents with respect to the most prominent AEs and the risk for less common but serious complications. Although treatment-associated AEs are common, the majority of AEs reported during clinical trial experiences were grade 1 or 2 in severity and manageable with intervention in the form of supportive measures and/or dosage modification. Therefore, despite the relatively complex AE profiles of RCC-directed targeted therapy, patient education, consistent monitoring with a focus on early detection by health care providers (oncologists, general physicians, nurses), and the application of emerging AE management strategies may allow for prolonged treatment in most patients with advanced RCC.
doi:10.1634/theoncologist.2011-S2-32
PMCID: PMC3868201  PMID: 21346038
Adverse event; Toxicity; Renal cell carcinoma; Kidney cancer; Vascular endothelial growth factor; Mammalian target of rapamycin; mTOR
23.  Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy 
Annals of Oncology  2011;23(6):1549-1555.
Background:
A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria.
Methods:
Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers.
Results:
One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors.
Conclusions:
Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.
doi:10.1093/annonc/mdr533
PMCID: PMC3858023  PMID: 22056973
primary refractory; renal cell carcinoma; VEGF; mTOR
24.  Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma: Clinical Evidence 
The Oncologist  2011;16(Suppl 2):14-22.
This article reviews the clinical evidence supporting the benefits of targeted agents in the treatment of metastatic renal cell carcinoma, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.
Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin-2 and interferon (IFN)-α, in recent years several targeted therapies have become available for first- and second-line use. These include sorafenib, sunitinib, bevacizumab (plus IFN-α), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular-targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow-up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression-free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.
doi:10.1634/theoncologist.2011-S2-14
PMCID: PMC3868199  PMID: 21346036
Angiogenesis inhibitor; Combination drug therapy; Mammalian target of rapamycin; Renal cell carcinoma; Vascular endothelial growth factor
25.  Systemic Therapy for Metastatic Non-Clear Cell Renal Cell Carcinoma: Recent Progress and Future Directions 
Renal cell carcinoma (RCC) encompasses a heterogeneous group of histological subtypes of which clear-cell RCC (CCRCC) is the most common comprising more than 70–80% of all cases. Papillary renal cell carcinoma (PRCC) is the next most common comprising 10–15% of cases. PRCC is refractory to chemotherapy, immunotherapy and hormonal therapy.
Insights into the biology of clear-cell RCC have identified multiple pathways associated with the pathogenesis and progression of this cancer. This has led to the development of multiple agents targeting these pathways including the small molecule tyrosine kinase inhibitors sorafenib, sunitinib and pazopanib, the monoclonal antibody bevacizumab and the mTOR inhibitors temsirolimus and everolimus. These drugs have shown significant clinical benefits in randomised trials in advanced CCRCC and have become the standard of care for most patients. With the exception of temsirolimus, phase III trials tested these agents in patients with clear-cell histology, and therefore, their efficacy in non-clear cell RCC is unclear. To date, there is no established effective therapy for patients with advanced non-clear cell RCC (NCCRCC). This review will focus on the treatment options of metastatic NCCRCC.
doi:10.1016/j.hoc.2011.05.003
PMCID: PMC4167832  PMID: 21763971
non-clear cell renal cell carcinoma; VEGF; mTOR; targeted therapy; papillary; chromophobe; unclassified; renal medullary carcinoma; collecting duct carcinoma; sarcomatoid dedifferentiation

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