REVIEW

Antiangiogenic treatments and mechanisms of action in renalcell carcinoma

Sylvie Négrier & Eric Raymond

Received: 4 March 2011 /Accepted: 26 April 2011 /Published online: 15 May 2011# Springer Science+Business Media, LLC 2011

Summary Several angiogenic mechanisms are involved inthe pathology of renal cell carcinoma (RCC). Increasingknowledge of angiogenesis and the associated signallingpathways has led to the development of targeted antiangio-genic agents for the treatment of metastatic RCC and theintroduction of these agents has significantly improvedoutcomes for these patients. This article provides anoverview of the angiogenic mechanisms implicated inRCC, focusing on the main vascular endothelial growthfactor (VEGF), platelet-derived growth factor (PDGF) andmammalian target of rapamycin (mTOR) signalling path-ways. Targeted antiangiogenic agents for the treatment ofmRCC include receptor tyrosine kinase inhibitors (such assunitinib, sorafenib, pazopanib, axitinib, cediranib andtivozanib), monoclonal antibodies (such as bevacizumab)and mTOR inhibitors (such as temsirolimus and ever-olimus). In this article, we consider the modes of action ofthese targeted agents and their differing target receptorprofiles and we also evaluate how these correlate with theirclinical efficacy and tolerability profiles.

Keywords Renal cell carcinoma . Angiogenesis . Targetedtherapy .Mode of action . Tolerability

Introduction

Historically, metastatic renal cell carcinoma (mRCC) has beenassociated with poor prognosis and resistance to chemother-apy. The introduction of immunotherapy achieved efficacy ina small subgroup of patients but carried toxicity concerns [1,2]. In recent years, elucidation of angiogenic mechanismshas led to the development of targeted antiangiogenic agents.Targeted agents have greatly improved outcomes in mRCCpatients and several have been approved multinationally forthe treatment of advanced and/or metastatic RCC. Currentlylicensed agents for the treatment of mRCC include sunitinibmalate (SUTENT®; Pfizer Inc.), temsirolimus (Torisel®;Pfizer Inc.), sorafenib (Nexavar®; Bayer Healthcare AG),bevacizumab (Avastin®; F. Hoffmann-La Roche Ltd) incombination with interferon-alpha (IFN-α), and everolimus(Afinitor®; Novartis Pharmaceuticals). Pazopanib (Votrient®;GlaxoSmithKline) recently received approval in the US andEurope. In addition, a number of novel agents—includingaxitinib, cediranib and tivozanib—are under investigation inclinical trials for the treatment of advanced RCC.

This paper provides an overview of the angiogenicmechanisms implicated in RCC, and discusses the modes ofaction of antiangiogenic agents and how these correlatewith their clinical profiles.

Angiogenic mechanisms underlying the pathologyof RCC

Several angiogenic mechanisms underlie the pathology ofsolid tumours. The switch to a pro-angiogenic environment

S. Négrier (*)Université de Lyon-Centre Léon Berard,28, rue Laennec,69373 Lyon cedex 08, Francee-mail: negrier@lyon.fnclcc.fr

E. RaymondDepartment of Medical Oncology and Laboratory ofPharmacobiology of Anticancer Drugs (RayLab),Bichat-Beaujon University Hospital,Paris, France

E. RaymondHôpital BEAUJON,100, Boulevard du Général Leclerc,92118 Clichy Cedex, France

Invest New Drugs (2012) 30:1791–1801DOI 10.1007/s10637-011-9677-6

can be induced by tumour-associated hypoxia, the activationof oncogenes, the inactivation of tumour-suppressor genes,and the secretion of a number of growth factors and cytokines[3, 4]. The pathways involved in RCC development includemainly the vascular endothelial growth factor (VEGF),platelet-derived growth factor (PDGF) and mammalian targetof rapamycin (mTOR) signalling pathways (Fig. 1) [5–7].

Vascular endothelial growth factor

VEGF expression is induced under hypoxic conditions [8]triggering several mechanisms that promote angiogenesis[9]. Members of the VEGF family regulate angiogenesisthrough binding to the related family of receptor tyrosinekinases (RTKs): VEGF receptors (VEGFR)-1, -2 and -3.The pro-angiogenic mechanisms of the VEGF signalingpathway have been well documented and are beyond thescope of this paper; readers are referred to a review by Ellisand Hicklin for a detailed discussion of this topic [9].

In RCC, VEGF is also a powerful tumour growth factor.Renal carcinoma cells over-express the different VEGFreceptors and also produce, as paracrine and autocrinegrowth factors, large amounts of VEGF [10].

Platelet-derived growth factor

The PDGF family (PDGF-A, -B, -C and -D) mediate theireffects through binding to the RTKs PDGF receptor-alpha

and -beta (PDGFR-α, PDGFR-β), leading to theactivation of intracellular signalling pathways that canpromote tumour growth [11, 12] Additionally, PDGFR-βis thought to be involved in the recruitment of pericytes tocapillaries [12]. Pericytes are required for microvascularstability and are important for maintaining tumourvasculature [13].

Few data have been published on PDGF and PDGFR inRCC. However, human RCC has been shown to expresshigh levels of PDGF-D, and PDGF-D over-expressionpromotes tumour growth, angiogenesis and metastasis inRCC [14]. Studies have also shown a relationship betweenRCC progression and PDGF-D/PDGFR-β signalling [14]and PDGFR-α expression [15].

Mammalian target of rapamycin

The mTOR pathway, including its role in RCC, has beenreviewed in several publications, to which readers arereferred for a more detailed discussion [16, 17] Hypoxia-induced activation of the mTOR pathway induces theexpression of several vascular growth factors, includingVEGF, VEGFR and PDGF, thus promoting tumourangiogenesis and endothelial proliferation [17, 18]. Inaddition to activation of the VEGF pathway, mTOR islargely involved in the AKT pathway, which is alsoderegulated in a number of tumour types including RCC[18, 19].

Fig. 1 Angiogenic pathways contributing to RCC growth and development, and the targeted agents that inhibit them [5–7]

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Modes of action of antiangiogenic agentsfor the treatment of mRCC

A number of antiangiogenic agents are in use or underinvestigation for the treatment of mRCC. Many of theseagents are multitargeted, inhibiting a range of targetsinvolved in tumour growth and angiogenesis (see Fig. 1)[5–7].

RTK inhibitors

The RTK inhibitors—sunitinib, sorafenib, pazopanib, axi-tinib, cediranib and tivozanib—inhibit multiple angiogenicpathways including the RTKs VEGFR and PDGFR and theRaf serine/threonine kinases (see Table 1) [20–34]. Theseagents share some similarities in their efficacy andtolerability profiles, as might be expected from their similarmodes of action. The aspects in which they differ mayreflect their varying target receptor profiles.

Sunitinib Sunitinib inhibits RTK autophosphorylation andligand-induced cell proliferation. It is thought that by inhibit-ing both VEGFR and PDGFR, ‘dual’ attack on the vasculature(via endothelial cells and pericytes) is achieved, thus leadingto greater antiangiogenic activity [9]. Oral sunitinib isapproved multinationally for the first- and second-linetreatment of advanced and/or metastatic RCC [35].

Sorafenib Sorafenib inhibits VEGFR, PDGFR, FMS-liketyrosine kinase 3 (Flt-3), c-Kit and RET receptor tyrosine

kinases. A study in RCC models reported significanttumour growth inhibition and a reduction in tumourvasculature with sorafenib, and antiangiogenic activitycorrelated with an increased level of tumour apoptosis andcentral necrosis [36]. Oral sorafenib is approved for thetreatment of advanced RCC in the US and for the treatmentof advanced RCC after cytokine failure in Europe [37].

Pazopanib Pazopanib inhibits VEGFR, PDGFR and c-Kit.In contrast to sunitinib and sorafenib (but similar toaxitinib), pazopanib demonstrates inhibitory activity atlow nanomolar concentrations [24, 28]. Studies in murinemodels have shown that pazopanib inhibits angiogenesisand tumour growth in a broad range of tumour types,including RCC [28, 38]. Pazopanib has recently beenapproved in the US for the treatment of advanced RCC[39] and has received conditional approval in Europe.

Axitinib Axitinib is a potent small-molecule RTK inhibitor;it inhibits VEGFRs at subnanomolar concentrations, andPDGFR-β and KIT at low nanomolar concentrations [29].Axitinib dose-dependently blocks VEGF-stimulated recep-tor autophosphorylation, leading to the inhibition ofendothelial cell proliferation and survival [29]. Axitinibalso reduces the extent of VEGF-mediated endothelial cellmigration and tube formation [29] Studies in mouse modelshave demonstrated the antitumour, antiangiogenic and anti-metastatic activity of axitinib and its ability to inducecentral necrosis [29, 40]. Axitinib is under investigation forthe second-line treatment of advanced RCC.

Table 1 Principal receptor targets of the antiangiogenic receptor tyrosine kinase inhibitors with activity in renal cell carcinoma

Receptor target

VEGFR-1

VEGFR-2

VEGFR-3

PDGFR-α

PDGFR-β

KIT FLT1 FLT3 FLT4 CSF-1R

RET Raf FGFR2

Approved agents

Sunitinib[20, 23,25–27, 35]

√ √ √ √ √ √ √ √ √

Sorafenib[21, 31]

√ √ √ √ √ √ √

Pazopanib[24, 28, 33]

√ √ √ √ √ √

Novel agents

Axitinib[29]

√ √ √ √ √

Cediranib[22, 30, 32]

√ √ √ √ √ √ √ √

Tivozanib[34]

√ √ √ √ √

VEGFR vascular endothelial growth factor receptor; PDGFR platelet derived growth factor receptor; KIT stem-cell factor receptor; FLT3 FMS-like tyrosine kinase-3 receptor, CSF-1R colony-stimulating factor 1 receptor; RET glial cell-line derived neurotrophic factor receptor (Rearrangedduring Transfection); FGFR2 fibroblast growth factor receptor 2

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Cediranib Cediranib (AZD2171) is an ATP-competitiveinhibitor of RTKs and, like axitinib, is potent atsubnanomolar concentrations [22, 30, 32]. Cediranibprevents VEGF-induced angiogenesis and exhibits dose-dependent antitumor activity through the prevention ofnew vessel formation and vascular regression [22, 32].Cediranib is under investigation for the treatment ofadvanced RCC.

Tivozanib Tivozanib (AV-951) is an RTK inhibitor, whichinhibits VEGFR-1, VEGFR-2 and VEGFR-3 at picomolarconcentrations. In xenograft tumour models, tivozanib hasbeen shown to inhibit tumour growth and angiogenesis[41]. Tivozanib is currently under investigation for the first-and second-line treatment of advanced RCC.

Monoclonal antibodies

Bevacizumab Bevacizumab, a recombinant humanisedmonoclonal antibody, binds directly to all biologicallyactive forms of VEGF [7] and shares some similaritieswith the RTK inhibitors in terms of clinical activity.Studies using xenograft models of a range of tumour typeshave shown dose-dependent inhibition of primary tumourgrowth with bevacizumab [42]. Bevacizumab has no effecton rates of tumour cell proliferation, supporting thehypothesis that this agent targets endothelial cell proliferationand disrupts neovascularisation [42, 43]. Bevacizumab isapproved multinationally, in combination with IFN-α, forthe first-line treatment of advanced and/or metastatic RCC[44].

mTOR inhibitors

Temsirolimus and everolimus are derivatives of the immu-nosuppressant agent rapamycin and both rapalogues inhibitthe mTOR angiogenic pathway. Preclinical data in RCCsuggest that the antitumour activity of mTOR inhibitorsmay be the result of a combination of two differentmechanisms: direct cytotoxic activity and indirect anti-angiogenic activity [17]. The cytotoxic activity of therapalogues against renal carcinoma cells is poor and dosedependent. In clinical trials with temsirolimus, toxicitylimited use of the higher doses tested using preclinicalmodels [17]. Antiangiogenic activity may be exerted byinterfering with the maintenance of endothelial cells andpericytes that are required for tumour angiogenesis [17]. Itis not clear which of these mechanisms predominates in theactivity of mTOR inhibitors in RCC, but it seems likely thatat current recommended doses, the efficacy of temsirolimusis mainly due to antiangiogenic activity.

Temsirolimus Temsirolimus forms a complex with theintracellular protein FKBP-12, and this protein-drug com-plex inhibits the activity of mTOR [17]. Temsirolimus,administered by intravenous injection, is approved inEurope as a first-line therapy for mRCC patients with poorprognosis and is approved in the US for the treatment ofmRCC [45].

Everolimus Everolimus also forms a complex with FKBP-12to inhibit mTOR and downstream signalling events. This inturn leads to growth retardation and antiangiogenesis, andaccumulation of cells in the G1 phase of the cell cycle [46].Everolimus has been shown to be effective in patients withmRCC after failure of sunitinib and/or sorafenib [47] and hasrecently been approved in Europe and the US for use in thissetting [48].

Antiangiogenic agents for mRCC in clinical practice

In the clinical setting, targeted agents for advanced RCCexhibit some similarities but also a number of differences intheir efficacy and tolerability profiles. These may beexplained, at least in part, by their modes of action anddiffering target receptor profiles.

Efficacy

The targeted agents have not been compared directly inclinical trials and comparisons between trials should bemade with caution. In addition, it is important to note thatthe trials with targeted agents included different patientpopulations, for example, some were conducted incytokine-refractory patients, while another trial enrolledpatients with poor prognosis mRCC [49, 50]. Nevertheless,data from phase III trials in advanced RCC, in both thefirst- and second-line settings, highlight some interestingobservations (Table 2) [47, 49–55].

Objective response rates In phase III clinical trials, theobjective response rates (ORR) achieved with agents thattarget the VEGF signalling pathway—i.e., sunitinib (39%),pazopanib (30%), bevacizumab plus IFN-α (26–31%) and,to a lesser extent, sorafenib (10%)—were higher than thoseassociated with agents that target the mTOR pathway(temsirolimus and everolimus [each <9%]; Table 2) [47,49–55]. It has been postulated that loss of VEGF signalling,with the associated endothelial cell apoptosis and vesselgrowth inhibition, may occur with VEGF-targeted thera-pies, such as sunitinib, pazopanib and bevacizumab/IFN-α,which are associated with higher response rates [9]. Thelower ORR achieved with sorafenib may be due to the fact

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that this agent was evaluated in the second-line setting (inpatients in whom previous therapy had failed). It could alsobe linked to the number of pathways (signal transduction)that are blocked by the drug, as illustrated by Karaman et alin a recent global analysis of multi-kinase activity [56].Additionally, it has been suggested that the lower ORR maybe due to the weaker binding affinity of sorafenib toVEGFR-2 and PDGFR-β compared with that of sunitinib[57].

Of note, preliminary data from phase II clinical trialsevaluating the efficacy of novel targeted agents in mRCCsuggest that these agents may have the potential to achievehigher ORRs than their older counterparts (Table 3) [58–60]. In the axitinib study in patients with cytokine-refractory RCC, the authors postulated that the level ofantitumour activity with axitinib (ORR 44%) may be due toits high potency against VEGFR1–3 [60].

Progression-freeandoverall survival Sunitinib (11.0 months),pazopanib (all patients: 9.2 months) and bevacizumab plusIFN-α (8.5–10.2 months) were associated with longermedian progression-free survival (PFS) than sorafenib(5.5 months) or the mTOR inhibitors (4.9–5.5 months) inclinical trials in mRCC (Table 2) [47, 49–55, 61]. Of note,the phase III randomised placebo-controlled study ofeverolimus was undertaken in patients with mRCC whohad progressed following other VEGF-targeted therapies[47]. The authors postulated that the efficacy of everolimusin this heavily pretreated population may have been due tothe distinct mechanism of action of mTOR inhibitors, and alack of clinical cross-resistance with VEGF inhibitors.

A meta-analysis evaluated investigator-assessed PFS inrandomised controlled trials of sunitinib, sorafenib, bev-acizumab and temsirolimus [62]. A total of five trials withtargeted agents as first-line therapy used IFN-α as thecomparator: the phase III sunitinib trial, the two phase IIItrials assessing bevacizumab plus IFN-α, the phase IIItemsirolimus trial in poor prognosis patients and thesorafenib phase II trial. Using indirect comparisons, withIFN-α as the common comparator, sunitinib was superior toboth sorafenib (HR: 0.58, 95% CI: 0.38–0.86, p<0.001)and bevacizumab plus IFN-α (HR: 0.75, 95% CI: 0.60–0.93, p=0.001), while sorafenib was not statisticallydifferent from bevacizumab plus IFN-α (HR:0.77, 95%CI: 0.52–1.13, p=0.21). Two trials used placebo as thecomparator: a phase II trial with bevacizumab alone incytokine-refractory patients and a phase III trial withsorafenib in cytokine-refractory patients. Using placebo asthe similar comparator, the authors found no significantdifference between sorafenib and bevacizumab alone (HR:0.81, 95% CI: 0.58–1.12, p=0.23). Temsirolimus providedsignificant PFS benefit in poor-prognosis patients (HR:0.69, 95% CI: 0.57–0.85).

In the first-line setting, sunitinib was associated withmedian overall survival (OS) of more than 2 years (Table 2)[54]. This represents the first time that this has beenachieved first-line in mRCC. Furthermore, when patientswho had received additional subsequent therapies wereomitted from the analysis, median OS was 28.1 monthswith sunitinib versus 14.1 months with IFN-α (p=0.0033)[54]. Median OS with bevacizumab plus IFN-α was 18.3and 23.3 months versus 17.4 and 21.3 months with IFN-α

Table 2 Efficacy data from phase III trials of targeted agents in the first- and second-line treatment of mRCC

Agent/comparator Setting N Median PFS, months Median OS, months ORR, %

Sunitinib vs. IFN-α [51, 54] First-line 750 11.0 vs. 5.1a 26.4 vs. 21.8 39 vs. 8a

Sorafenib vs. placebo [50] Second-line 903 5.5 vs. 2.8a 17.8 vs. 15.2 10 vs. 2a

Pazopanib vs. placebo [55, 65] First- and second-line 435 9.2 vs. 4.2a 22.9 vs. 20.5 30 vs. 3a

Bevacizumab+IFN-α vs. IFN-α [53, 63] First-line 649 10.2 vs. 5.4a 23.3 vs. 21.3 31 vs. 13a

Bevacizumab+IFN-α vs. IFN-α [52, 64] First-line 732 8.5 vs. 5.2a 18.3 vs. 17.4 26 vs. 13a

Temsirolimus vs. IFN-α [49] First-line 626 5.5 vs. 3.1a 10.9 vs. 7.3a 8.6 vs. 4.8

Everolimus vs. placebo [47, 61] Second-line 410 4.9 vs. 1.9a 14.8 vs. 14.4 1 vs. 0

PFS progression-free survival; OS overall survival; ORR objective response rate; IFN-α interferon-alpha; Bev bevacizumab; NR not reacheda Statistically significant

Targeted agent Patient population Response rate, % Disease control rate, %

Axitinib [60] Cytokine-refractory mRCC 44 69

Axitinib [59] Sorafenib-refractory mRCC 23 40

Cediranib [58] Treatment-naïve advanced RCC 38 84

Tivozanib [72] No prior VEGF-targeted therapy 27 84

Table 3 Response rates fromphase II clinical trials of axitiniband cediranib

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alone (p=0.097 and p=0.1291) [63, 64]. Recently pre-sented data showed that median OS was 22.9 months withpazopanib in both treatment-naïve patients and those withcytokine-refractory disease versus 20.5 months with placebo(p=0.224). However, the OS analysis may have beenconfounded by frequent crossover of patients from theplacebo group to the pazopanib group [65].

Median OS achieved with sorafenib in the second-linesetting was 17.8 months versus 15.2 months with placebo(p=0.146) [66]. When these data were censored for patientswho switched from placebo to sorafenib, median OS was17.8 months with sorafenib versus 14.3 months withplacebo (p=0.0287) [66]. Median OS with everolimus inpatients who had progressed on VEGF-targeted therapieswas 14.8 months versus 14.4 months with placebo (p=0.162)[61]. Similar to other trials, patient crossover from placebo toeverolimus may have confounded the OS data [61].

In poor-prognosis patients, temsirolimus achieved medi-an OS of 10.9 months versus 7.3 months with IFN-α (p=0.008) [49]. A post-hoc analysis from the phase III ARCCstudy [49] indicated that temsirolimus also improves OS inpatients with histologies other than clear-cell RCC (themajority of these patients had papillary histologies),suggesting that it can be used for the treatment of all typesof RCC [67]. This finding could be explained by thedifference in carcinogenesis between papillary and clear-cell renal tumours. The importance of VEGF-driven growthin clear-cell tumours easily explains their sensitivity to anti-VEGF agents [68] whereas this mechanism is not predom-inant in the papillary subtype [69, 70]. On the contrary,papillary tumours over-express cMet and PTEN, two genesthat are closely related to mTOR activation status [71].

As noted for ORR, PFS and OS rates achieved withinvestigational drugs in phase II trials were longer thanthose achieved with more established agents in this class.Median OS with axitinib in cytokine-refractory mRCC was30 months, with a 1-year survival rate of 79% [60]. MedianPFS with cediranib in treatment-naïve patients was8.7 months, reflecting findings with comparable targetedagents in mRCC [58]. Similarly, tivozanib was associatedwith median PFS of 11.8 months in a phase II trial whichenrolled patients who had received no prior antiangiogenictherapy [72]. Further data from randomised phase III trialsare required to support these findings. Whilst direct compar-isons between agents are problematic due to inter-trialdifferences, these observations are interesting nonetheless.

Tolerability of the antiangiogenic agents in clinical practice

The tolerability profiles of the targeted agents bear anumber of similarities, as might be expected from theirmechanisms of action, but also some potentially clinically

significant differences (Table 4) [47, 49–55]. Adverseevents (AEs) that are believed to be due to VEGF inhibitioninclude hypertension [73, 74], haemorrhage [75], mucositis,skin toxicity (including hand–foot syndrome), hypothyroid-ism [76–79], and fatigue [80]. AEs attributable to theinhibition of PDGF include skin reactions [81]. Inhibitionof mTOR has been associated with a distinct pattern of skintoxicity (acne-like and maculopapular rashes) [82, 83].Specific AEs of particular interest are discussed furtherbelow.

Hypertension Anti-VEGF activity has been associated withhypertension, and clinical trials with the targeted agentssunitinib, sorafenib, bevacizumab, axitinib, pazopanib,cediranib and tivozanib have all shown incidences oftreatment-related hypertension [35, 37–39, 44, 52, 72, 84].

Several studies with VEGF inhibitors have demonstratedreduced tumour perfusion after treatment administration[85, 86], possibly representing vasoconstriction as a resultof decreased production of vasodilatory mediators. Suchvasoconstriction could lead to tumour ischemia andnecrosis, and could be important in RCC. As the vasocon-strictive effects of VEGF inhibitors are not limited to thetumour vasculature, researchers have postulated that hyper-tension may represent a surrogate marker of antitumouractivity in RCC, and preliminary data support this hypothesis[9]. Indeed, blood pressure was shown to be associated withlonger OS in a retrospective analysis of data from sixaxitinib studies [87]. Furthermore, a significant associationbetween hypertension and improved clinical outcome withsunitinib has been shown, suggesting that this may be a drugclass effect for tyrosine kinase inhibitors [88].

Haemorrhage/necrosis Both VEGF and mTOR inhibitionhave been associated with bleeding events and rarely withtumour haemorrhages in patients with mRCC [35, 37, 39,44, 48]. Bleeding events may manifest as epistaxis,hemoptysis, or rectal, gingival, upper gastrointestinal,genital, or wound bleeding. VEGF plays an important rolein maintaining vascular integrity by enhancing proliferationand survival of endothelial cells. Inhibition of VEGF maytherefore reduce the regeneration of endothelial cellsfollowing trauma, thus increasing the risk of bleeding [73].

Hand-foot syndrome Hand–foot syndrome is reportedcommonly in patients receiving treatment with sunitiniband, particularly, sorafenib [35, 37]. Neither the VEGF-binding agent bevacizumab nor the mTOR inhibitorstemsirolimus and everolimus are associated with this typeof toxicity [44, 45, 48].

Fatigue Fatigue is common in cancer patients treated withtargeted agents, but may also be due to disease and other co-

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morbidities such as hypothyroidism, anaemia and depression.VEGF is known to be involved in thyroid functioning but it isnot known if inhibition leads to hypothyroidism and causesfatigue [23, 77, 89]. The development of hypothyroidismduring sunitinib and sorafenib treatment has been shown tobe an independent predictor of survival and may be a usefulas a clinical predictor of PFS [90].

Fatigue is commonly observed with the tyrosine kinaseinhibitors, sunitinib and sorafenib [50, 51, 54]. Grade 2–3fatigue has been reported with everolimus but not withtemsirolimus [91]. The potential relationship betweenmTOR inhibition and fatigue is not clear.

Cardiotoxicity Varying degrees of cardiotoxicity have beenreported with the tyrosine kinase inhibitors sunitinib andsorafenib [92]. HIF-1—a target for these agents—has beenshown to slow the progression of myocardial dysfunctionafter myocardial infarction, and inhibition may thereforeaffect cardiac function [93–95].

Pneumonitis Pneumonitis has been reported with bothtemsirolimus and everolimus, with a higher incidenceobserved in patients receiving everolimus [45, 47]. Themechanisms involved in the development of pneumonitisduring treatment with temsirolimus and everolimus havenot yet been determined.

Conclusions and future perspectives

Historically, mRCC has been associated with treatmentresistance and poor prognosis. However, increasing knowl-edge of angiogenesis and associated signalling pathways,and the subsequent development of antiangiogenic thera-pies have exerted a substantial impact on outcomes forpatients with mRCC. The targeted antiangiogenic agentssunitinib, sorafenib, pazopanib, bevacizumab (in combinationwith IFN-α), temsirolimus and everolimus are approved forthe treatment of advanced RCC. Each agent is unique in termsof its antiangiogenic and antitumor activities and the receptortargets with which it interacts, resulting in unique efficacy andsafety profiles. In addition, a number of novel agents are indevelopment, including axitinib, cediranib and tivozanib, withpreliminary data suggesting substantial antitumour activity inmRCC.

Ongoing and future trials will aim to further characterisethe efficacy and tolerability profiles of the approved andnovel agents in mRCC, investigating their activity acrossdifferent patient profiles and in combination and insequence in order to optimise patient management in thissetting. A number of clinical studies are in progress toinvestigate the efficacy and safety of such strategies. A lackof cross resistance between the targeted antiangiogenicinhibitors has been observed, suggesting that sequential

Table 4 Incidence and severity of commonly reported adverse events associated with targeted agents for the treatment of mRCC

Selected toxicity Percentage incidence for each targeted agent, all grades (grades 3–4)a

Sunitinib[54]

Sorafenib[50]

Pazopanib[55]

Bevacizumab+IFN-α[53]

Temsirolimus[49]

Everolimus[47]

Arterial hypertension 30 (12) 17 (4) 40 (4) 26 (3) – –

Asthenia 20 (7) – 14 (3) 32 (10) 51 (11) 18

Bleeding/Epistaxis 18 (1) – – 33 (3) – –

Diarrhea 61 (9) 43 (2) 52 (4) 20 (2) 27 (1) 17

Fatigue 54 (11) 37 (5) 19 (2) 33 (12) – 20 (3)

Hand–foot syndrome 29 (9) 30 (6) – – – –

Mucositis 26 (2) – – – – 14

Pneumonitis – – – – – 8 (3)

Hematological abnormalities/renal toxicities

Anemia 79 (8) 8 (3) – 10 (3) 45 (20) 91 (9)

Leucopenia 78 (8) – 37 (0) – 6 (1) 26 (0)

Neutropenia 77 (18) – 34 (1) 7 (4) 7 (3) 11 (0)

Thrombocytopenia 68 (9) – 32 (1) 6 (2) 14 (1) 20 (<1)

Proteinuria – – – 18 (7) – –

Increased creatinine 70 (<1) – – – 14 (3) 46 (<1)

Increased creatinekinase

49 (3) – – – – –

NR not reporteda Reported in ≥10% of patients for sunitinib, pazopanib and everolimus; ≥10% for grade 1–2, ≥2% for grade 3–4 for sorafenib; ≥10 of and ≥30%for clinical laboratory abnormalities for pazopanib; ≥2% for bevacizumab+IFN-α; ≥20% for temsirolimus

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therapy may be effective [96]. Several trials, including theAGILE 1032 trial comparing axitinib and sorafenib assecond-line treatment and the 404 study comparing temsir-olimus and sorafenib in patients who have progressedfollowing first-line sunitinib, are ongoing and may providefurther information regarding optimal sequencing of agents[97]. In contrast, previous studies have suggested thatcombination treatments are not always well tolerated [98].However, the simultaneous inhibition of both VEGF andmTOR with bevacizumab and temsirolimus is beingassessed in an ongoing trial [97].

Acknowledgements Editorial support for this manuscript wasprovided by Cherry Bwalya and Caroline Masterman at ACUMED(Tytherington, UK) and was funded by Pfizer, Inc.

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