1. Introduction

2. Body of review

3. Overview of the market

4. Introduction to the compound

and chemistry

5. Preclinical data,

pharmacokinetics and

pharmacodynamics

6. Clinical efficacy in breast

cancer

7. Safety and tolerability

8. Biomarkers

9. Expert opinion

Drug Evaluation

Pazopanib for the treatment ofbreast cancerLaleh Amiri-Kordestani, Antoinette R Tan & Sandra M Swain††Washington Cancer Institute, MedStar Health, Washington Hospital Center, Washington, DC, USA

Introduction: Several clinical trials have shown clinical benefit of angiogenesis

inhibitors in the treatment of solid tumors. Pazopanib is a multitargeted tyro-

sine kinase inhibitor that is currently approved for the treatment of patients

with advanced renal cell carcinoma (RCC).

Areas covered: In this article, the clinical development of pazopanib as it

relates to breast cancer is reviewed including its evaluation in clinical trials

and side effect profile. Preclinical data show the anti-tumor activity of

pazopanib in animal models. Several trials of pazopanib monotherapy and

combination therapy in breast cancer have been completed or are underway.

Expert opinion: The development of biomarkers predictive of response and

toxicity to angiogenesis inhibitors remains a challenging endeavor and is

necessary to help guide treatment decision.

Keywords: breast cancer, pazopanib, PDGFR, tyrosine kinase inhibitor, VEGF, VEGFR

Expert Opin. Investig. Drugs (2012) 21(2):217-225

1. Introduction

Breast cancer is the second leading cause of cancer mortality among women in theUSA [1]. Endocrine therapy and chemotherapy have provided significant benefit,but despite recent advances in systemic therapy, there has been only a modestimprovement in survival [2]. Novel therapeutic approaches are needed toimpact outcome.

Angiogenesis is an important step in the growth of cells and their transition tomalignancy [3]. There is preclinical evidence that microvessel density as a surrogatefor angiogenesis correlates with metastasis in breast cancer and is an independent neg-ative prognostic factor [4,5]. Expression of vascular endothelial growth factor (VEGF)as a prototypic angiogenic factor is increased in invasive breast cancers [6,7]. VEGF hasbeen reported to correlate negatively with survival in patients with breast cancers,regardless of whether they have received adjuvant therapy [8-13]. VEGF’s functionsare mediated by binding to one of the three receptor tyrosine kinases (VEGFR-1,VEGFR-2 and VEGFR-3) [14]. Studies have shown that breast cancer cells expressVEGFR-1 and VEGFR-2 [15,16] and VEGF signals mainly through VEGFR-2 [16-18].

Platelet-derived growth factor (PDGF) is another angiogenic growth factor, thatis synthesized and secreted by breast cancer cell lines [19] and increases theirgrowth [20]. Immunohistochemical studies have shown PDGF expression in phyllo-des breast cancer with PDGFR-a [21] and PDGFR-b [22] expression occurring pre-dominantly in stromal cells [23]. Increased levels of PDGF either in plasma [24] orbreast tissue by immunohistochemistry staining [25,26] correlates negatively with sur-vival. Also, high stromal PDGFR-b expression correlates significantly with shortersurvival in patients with primary breast cancer [27].

2. Body of review

The primary aim of this review is to provide a detailed overview of pazopanib and itsrole in the treatment of breast cancer (Box 1). The PubMed database was searched

10.1517/13543784.2012.652304 © 2012 Informa UK, Ltd. ISSN 1354-3784 217All rights reserved: reproduction in whole or in part not permitted

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for articles published in the English language up to August2011. Abstracts presented at the American Society of ClinicalOncology and American Association for Cancer Researchconferences from 2008 to 2011 were searched. The key termsused were ‘pazopanib’, ‘VEGF’, ‘PDGF’ and ‘breast cancer’.

3. Overview of the market

There are several anti-angiogenic agents that are in variousstages of development for the treatment of breast cancer(Table 1). There are currently no small molecule tyrosinekinase inhibitors that target VEGF which are approvedfor breast cancer. Sorafenib [28,29], sunitinib [30-32] andvandetinib [33] are approved by the US Food and DrugAdministration (FDA) for other indications.

4. Introduction to the compound andchemistry

Pazopanib (GW786034, Votrient�; GlaxoSmithKline, Phila-delphia, PA, USA) is a novel 2H-indazolylpyrimidine com-pound (Figure 1). It was synthesized after initial screening ofa chemical precursor identified its ability to inhibitVEGFR-2. In vitro kinase assays have established its activityagainst VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a,PDGFR- b and c-Kit (Table 2) [34].

5. Preclinical data, pharmacokinetics andpharmacodynamics

Pazopanib competes with adenosine triphosphate (ATP) forbinding to the intracellular site of tyrosine kinase receptors.A component of the pazopanib structure, that mimics the ade-nine ring of ATP, forms hydrogen bonds with the receptor,inhibiting ATP-induced activation. Pazopanib inhibitsVEGF-induced proliferation of human umbilical vascularendothelial cell and VEGF-induced phosphorylation ofVEGFR-2 in those cells with an IC50 of 8 nM [34,35].In various human tumor xenograft models, pazopanib anti-

tumor activity has shown a dose-dependent growth inhibi-tion. Maximal growth inhibition was 99 and 64% in renalcell carcinoma (RCC) and breast cancer xenografts,

respectively [36]. Pazopanib has also been tested in the preven-tion of experimental brain metastases in HER2 transfectedbrain-seeking sublines. Twenty-one days of oral administra-tion of pazopanib (100 mg/kg) resulted in a 39% reductionin micrometastases (p = 0.004) and a 73% reduction inmacrometastases (p < 0.0001) in mice brains [37].

The pharmacokinetics of a pazopanib analog with a similarenzyme and cellular profiles to pazopanib was evaluated bycomparing two different routes of administration (bolus peros (po) dosing and continuous intravenous infusion) andwas found that a steady-state concentration was required foroptimal in vivo activity [36].

The steady-state exposure of pazopanib plateaued atdoses ‡ 800 mg/day and the mean target trough concentra-tion was achieved at 800 mg/day. The mean eliminationhalf-life at 800 mg dose was 31.1 h at day 22. This doseresulted in an AUC 0 -- 24 of 743.3 µg h/ml and Cmax

45.1 µg/ml [38]. The bioavailability and rate of pazopanibabsorption were increased after administration of the crushedtablet relative to the whole tablet [39]. Administration of pazo-panib with a high-fat or low-fat meal almost doubled the Cmax

and AUC [40].Pazopanib is a substrate for p-glycoprotein and breast can-

cer resistance protein. It is metabolized primarily by CYP3A4,with very little contribution of CYP1A2, CYP2C8 andCYP2D6. Pazopanib inhibits activities of CYP enzymes3A4, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 and may induceCYP3A4 activity [34,41]. Pazopanib also inhibits UGT1A1and OATP1B1 (Table 3) [42,43].

6. Clinical efficacy in breast cancer

Pazopanib was approved by the US FDA in October2009 and the European Medicines Agency in June 2010 forthe treatment of patients with advanced RCC [44]. It isundergoing evaluation for breast cancer.

6.1 Phase IThere are several Phase I studies of pazopanib (Table 4); onlythose relevant to the treatment of breast cancer will bediscussed here.

Hurwitz et al. [38] conducted a Phase I study of pazopanibin 63 patients with solid tumors, including 5 patients withbreast cancer. There were two sequential cohorts. Forty-three patients were enrolled to a dose escalation cohort and20 patients were enrolled into an expansion cohort. Dose-limiting toxicities (DLTs) occurred at 50, 800 and 2000 mgin the once daily dose levels. DLTs were grade 3 gastrointesti-nal bleeding, extrapyramidal involuntary movements, hyper-tension and fatigue. There was also one grade 4 pulmonaryembolism. The maximum tolerated dose in this study wasnot reached. With doses ‡ 800 mg/day steady-state exposurehad plateaued and 93% of patients achieved day22 C24 values of ‡ 15 µg/ml, a dose that correlated withthe pharmacodynamic effect of hypertension. This dose was

Box 1. Drug summary.

Drug name PazopanibPhase (for indicationunder discussion)

Currently in Phase I -- III

Mechanism of action Multitargeted tyrosine kinaseinhibitor

Route of administration OralChemical name 5-[[4-[(2,3-Dimethyl-2H-indazol-

6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide [34]

Pivotal trial NCT00558103

Pazopanib

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safe and tolerable and was recommended for future Phase IIstudies. Two partial responses (PRs) in RCC (300 mg/daytwice and 1400 mg/day dose) and one PR in pancreatic isletcell tumor (1000 mg/day dose) were seen. No responses orstable diseases (SDs) were seen in the patients with breastcancer [38].

In a Phase I study of weekly paclitaxel combined with dailypazopanib, 26 patients with advanced solid tumors including5 patients with metastatic breast cancer were enrolled. DLTsincluded grade 2 hyperbilirubinemia and a grade 3 abscess.The recommended Phase II dose was determined to be pazo-panib 800 mg/day and paclitaxel 80 mg/m2 given on days 1,8 and 15 on a 28-day cycle. There were five confirmed PRs,including breast cancer (two), non-small cell lung carcinoma

(one), ovarian cancer (one) and esophageal cancer (one).Among the five breast cancer patients, two patients withtriple-negative tumors achieved PRs as their best response [45].

The administration of paclitaxel and carboplatin every21 days in combination with daily pazopanib has been evalu-ated in two separate studies [46]. A Phase I study treated34 patients, including 10 with metastatic breast cancer. Inthis study, the DLTs were grade 3 and 4 neutropenia, grade1, 3 and 4 thrombocytopenia, grade 3 hypertension, grade2 pneumonia and grade 3 infections. The optimum toleratedregimen (OTR) was paclitaxel 175 mg/m2 and carboplatinAUC 5 every 21 days and pazopanib 200 mg p.o. daily. Therewere complete responses in two patients with esophageal can-cer and eight patients with PRs. Of the 10 metastatic breastcancer patients, 3 had ‡ 3 prior lines of therapy with PR astheir best response.

The second study was a two-arm Phase I/II study in previ-ously untreated patients with gynecological malignancies.Two arms were designed to test different doses of carboplatinAUC5 versus 6 in a non-randomizedway. Grade 4 and 5 bowelperforations were observed in the carboplatin AUC 5 arm,which did not permit enrollment to the carboplatin AUC6 arm. A pharmacokinetic interaction was observed. Cmax ofpaclitaxel in the presence of pazopanib 400 and 200 mgincreased 40 and 43%; clearance decreased by 17 and 30%;AUC 0 -- 23 of carboplatin increased by 31 and 41% andCmax increased by 68 and 54%, respectively. Due to the intol-erability of the regimen, the OTR could not be defined [46].Although this study had no patients with breast cancer, it wasdiscussed to rationalize the design and schedule of an ongoingPhase I study (NCT01407562) [47] with same drugs but a dif-ferent schedule to decrease the toxicities. This study is beingconducted to assess the safety and tolerability of paclitaxeland carboplatin given weekly in combination with pazopanibdosed on an intermittent schedule and is currently accruingsolid tumor patients with an accrual goal of 45 and is plannedto have an expansion cohort for patients with breast cancer. Inthis study, pazopanib is given on days 2 -- 5, 9 -- 12 and 16 -- 26;paclitaxel and carboplatin are given on days 1, 8 and 15, of a28-day cycle with starting doses of 400 mg, 60 mg/m2 and anAUC of 2, respectively [48].

In another Phase I study, the safety and tolerability of pazo-panib and lapatinib was studied for patients with advancedsolid tumors. The results revealed that the regimen was welltolerated, but a full report is not available [49]. A Phase I clin-ical trial of the combination of paclitaxel, lapatinib and pazo-panib has been completed, but data have not been presented(Table 4).

The combinations of epirubicin or doxorubicin with pazo-panib are being studied in a Phase Ib trial with four arms [50].In arms A, B and C, pazopanib and epirubicin are adminis-tered on days 1 -- 21 and day 3, days 1 -- 8 and day 3 anddays 14 -- 21 and day 1, respectively. For arm D, the plan isto pick the best schedule and study doxorubicin insteadof epirubicin.

Table 1. Anti-angiogenic agents.

Agent Major molecular targets

Aflibercept VEGF-A, VEGF-B, PlGFAxitinib VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, c-KitBevacizumab VEGF-ACediranib VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, c-KitE-3810 VEGFR-1, VEGFR-2, VEGFR-3, FGFR-1, FGFR-2Motesanib VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, c-Kit, RETPazopanib VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, c-KitPTC299 VEGF expression inhibitorSorafenib VEGFR-2, VEGFR-3, PDGFR, RafSunitinib PDGFR, VEGFR-1, VEGFR-2, VEGFR-3, c-Kit,

FLT-3, RETVandetinib VEGFR-2, EGFR, c-Kit, RETVatalanib VEGFR-1, VEGFR-2, PDGFR, c-Kit

Me

SO2NH2

HN N

N

NN

N Me

Me

Me

Figure 1. Structure of pazopanib [34].

Table 2. Pazopanib in vitro activity.

Pazopanib IC50 (mmol/l) [36]

VEGFR-1 0.010VEGFR-2 0.030VEGFR-3 0.047PDGFR-a 0.071PDGFR-b 0.084c-Kit 0.074

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Preliminary data of arms A, B and C were presented for thefirst 60 patients; including 11 patients with breast cancer outof a planned 78 estimated enrollment. The pazopanibdose was started at 200 mg and escalated to 800 mg. Epirubi-cin starting dose was 60 mg/m2 and it was increased to90 mg/m2. Grade 4 neutropenia, grade 4 anemia, grade3 aspartate aminotransferase (AST) elevation, grade 3 asthenia,grade 3 dehydration, nausea and vomiting and grade 3 deepvenous thromboses were reported to be DLTs for this regi-men. There were 51 patients evaluable for response. Eightpatients had PRs (5 from arm A, 2 of this 5 patients hadbreast cancer). Selected doses for expansion phase in arm Aare pazopanib 400 mg and epirubicin 75 mg/m2; in arm Band C is pazopanib 800 mg and epirubicin 90 mg/m2

[51].Pazopanib is also being evaluated in Phase I clinical trials in

combination with ixabepilone, vinorelbine and cisplatin,which are drugs that have a role in the treatment of metastaticbreast cancer (Table 4).

6.2 Phase IIThe efficacy of pazopanib in metastatic breast cancer has beenstudied in a single arm open-label multicenter Phase IItrial [52]. Patients with recurrent or metastatic breast cancer,who received up to two prior lines of chemotherapy (includ-ing neoadjuvant or adjuvant) were recruited from three cen-ters in Canada. Pazopanib was given at 800 mg/day. In20 evaluable patients, the majority of tumors were estrogenreceptor positive, and none were HER2 positive. One patientwith ER-positive breast cancer who had only prior adjuvantchemotherapy had a confirmed PR. The median time to pro-gression was 5.3 months. Grade 3 and 4 toxicities that wereobserved in ‡ 10% of patients included: elevations in liverenzymes, hypertension, and leukopenia (lymphopenia andneutropenia). Diarrhea, fatigue and skin/hair hypopigmenta-tion developed in 62, 57 and 57% of patients, respectively.There was one grade 4 adverse event of alanine aminotransfer-ase elevation that had normalized after stopping pazopanib.The trial was closed to accrual after stage one as it did notmeet the predefined criteria for efficacy.In another Phase II study, the efficacy of dual VEGF/

HER2 blockade with pazopanib and lapatinib as first-line therapy in HER2 positive advanced or metastatic breastcancer was evaluated. In Cohort 1 of this study, 69 patientswere randomized to the combination of pazopanib 400 mg/day and lapatinib 1000 mg/day and 72 patients to lapatinibalone given at 1500 mg/day. In cohort 2, patients received

pazopanib 800 mg/day and lapatinib 1500 mg/day. The pri-mary end point of cohort 1 was progressive disease rate atweek 12. The primary end point of cohort 2 was responserate at week 12. The study is completed, but not yet pub-lished. Preliminary results show that in cohort 1, the additionof pazopanib to lapatinib did not improve progressive diseaserate at week 12 (38.9 vs. 36.2%, p = 0.37). A higher incidenceof grade 3 and 4 adverse events was observed in the combina-tion arm [53]. Data for cohort 2 indicated that the higher doseof this combination resulted in similar response rate to thelower dose of combination arm in cohort 1. Due to thehigh incidence of grade 3 and 4 diarrhea (40%), the highercombination dose was not tolerable [54].

In neoadjuvant setting, there are two Phase II studies withpathological complete response as their primary end point.NSABP FB-6 trial evaluates the combination of doxorubicinand cyclophosphamide followed by weekly paclitaxel concur-rent with pazopanib. Four to 6 weeks after surgery pazopanibis restarted and is given for 6 months. The outcome data areawaited [55]. The second study evaluates the combination ofanastrozole and pazopanib (Table 5).

In a pilot Phase II study, pazopanib has been studied inpatients with lymphedema following breast cancer treatment.Ten patients received pazopanib 800 mg/day. Mean intersti-tial fluid pressure in the affected arm decreased an averageof 76% 24 h after initiation of pazopanib (5.73 vs.1.56 mm Hg; p = 0.0061) [56].

6.3 Phase IIIA multicenter Phase III study evaluating the combination ofpazopanib and lapatinib in patients with HER2 positiveinflammatory breast cancer (IBC) has completed accrual (esti-mated 360 patients). Increased VEGF receptors have beenshown in IBC [57]. In a Phase II study, single agent lapatinibfor treatment for relapsed or refractory HER2 positive IBChad a 49% PR rate [58]. As pazopanib is a VEGF tyrosinekinase inhibitor, combining these two mechanisms seems tohave a potential in this setting.

This study enrolled patients into two cohorts. In cohort 1,combination of pazopanib and lapatinib was compared withlapatinib and placebo in a randomized double blind way.Cohort 2 has three arms and in an open-label fashion com-pared the combination of lapatinib and pazopanib versus sin-gle agent lapatinib versus single agent pazopanib. The primaryend point of the study is progression-free survival, withoutcome data awaited [59].

7. Safety and tolerability

Overall, the adverse effects of pazopanib are similar to otheranti-angiogenic agents. The largest published study of pazopa-nib monotherapy is a Phase III trial in RCC. All grade toxic-ities with an incidence > 30% in pazopanib arm andplacebo arm included: elevation of liver enzymes (53, 22%),diarrhea (52, 9%), hyperglycemia (41, 33%), hypertension

Table 3. Pharmacokinetics of pazopanib.

Bioavailability OralProtein binding > 99%Metabolism Hepatic mainly via CYP3A4Excretion Feces, < 4% renalHalf-life 31 h

Pazopanib

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(40, 10%), hair color changes (38, 3%), leukopenia (37, 6%),hypophosphatemia (34, 11%), increased total bilirubin(36, 10%), neutropenia (34, 6%), hypocalcemia (33, 26%),thrombocytopenia (32, 5%), lymphocytopenia (31, 24%)and hyponatremia (31, 24%), respectively. Grade 4 toxicitiesthat were observed were ALT elevation, hypocalcemia andhyponatremia, diarrhea, vomiting, AST increase, total biliru-bin increase, hypoglycemia, neutropenia, thrombocytopenia,lymphopenia. Rarely, pazopanib causes hypothyroidism, arte-rial thrombosis, fatal hemorrhage, proteinuria, gastrointesti-nal perforation, QT prolongation, torsades de points andlate surgical dehiscence [44,60].

In a meta-analysis, the incidence of hepatotoxicity due topazopanib was assessed. A total of 1155 patients with majorityof patients with RCC from eight prospective clinical trialswere included. The incidence of all-grade ALT and AST ele-vation were 41.7% (95% confidence interval (CI) 33.9 to49.9%) and 39.3% (95% CI 30.2 to 49.2%), with 8.2%(95% CI 5.9 to 11.3%) and 6.4% (95% CI 4.6 to 8.8%)being grade 3 and 4, respectively [61]. Pazopanib-inducedhyperbilirubinemia has been associated with a polymorphismof UGT1A1 [42]. Polymorphism in the hemochromatosis geneis associated with an elevation of ALT [62].

Prescribing information for pazopanib recommendsmonitoring serum liver tests before initiation of treatment

and every 4 weeks for at least the first 4 months of treatment.After this, periodic monitoring is recommended [43].

Pazopanib may cause hair and skin depigmentation. Skinhypopigmentation develops after one to two cycles of pazopa-nib and decreases with dose reduction or discontinuation ofpazopanib [63,64]. In a meta-analysis, the incidence of handfoot skin reaction (HFSR) was investigated in 10 prospectiveclinical trials. The overall incidence of all-grade andgrade 3 HFSR was 4.5% (95% CI 2.5 to 7.9%) and 1.8%(95% CI 0.7 to 4.6%), respectively [65].

8. Biomarkers

As outlined in the above studies, response and tolerability topazopanib varies. Xu et al. studied the germline genetic var-iants in 397 RCC patients. They found three polymorphismsin IL-8 and HIF1A that were significantly associated with PFSand five polymorphisms in HIF1A, NR1l2 and VEGFA thathad significant association with response rate [66]. In anotherstudy, broad profiling of 31 cytokines and angiogenic factorswere measured before the start of pazopanib and on last day oftherapy in 33 patients with early non-small cell lung cancer.They reported baseline levels of 11 of these 31 factors signif-icantly correlated with response, with IL-12 having thestrongest association [67]. Endoglin and placental growth

Table 4. Phase I trials.

Agents Study identifier Study population # Patients Status

Pazopanib + Vinorelbine NCT01060514 [73] Metastatic non-small celllung cancer and breast cancer

15 R

Pazopanib + Ixabepilone NCT01012362 [74] Solid tumors 27 SPazopanib + Epirubicin or Doxorubicin NCT00722293 [75] Advanced solid tumors 110 RPazopanib + Cisplatin NCT01165385 [76] Advanced solid tumors (TNBC cohort) 38 RPazopanib NCT00060151 [77] Solid tumors 63 CPazopanib + PaclitaxelPazopanib + Paclitaxel + CarboplatinPazopanib + Paclitaxel + Lapatinib

NCT00388076 [78] Solid tumors 86 C

Pazopanib + Paclitaxel + Carboplatin NCT01407562 [79] Solid tumors 45 RPazopanib + Lapatinib NCT00158782 [80] Advanced, refractory solid tumors 65 C

C: Completed; R: Recruiting; S: Suspended.

Table 5. Phase II trials.

Arm(s) Study identifier Study population # patients Status

Anastrozole + Pazopanib NCT01394211 [81] Stage II and III ER+ breast cancer 50 RPazopanib NCT00509587 [82] Recurrent and/or metastatic breast cancer 35 APazopanib + Lapatinibvs. Lapatinib

NCT00347919 [83] First-line therapy, HER2+ locally advancedor metastatic breast cancer

189 A

Pazopanib + Exemestanevs. Exemestane + Placebo

NCT00615524 [84] Postmenopausal, advanced or metastatic,hormone receptor positive breast cancer

- T

Doxorubicin+ CyclophosphamideFollowed by Paclitaxel + Pazopanib

NCT00849472 [85] Locally advanced breast cancer 101 A

A: Active, not recruiting; R: Recruiting; T: Terminated.

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factor (PiGF) also have been reported as potential biomarkersfor pazopanib exposure and activity in pediatric patients, butvalidation is warranted in larger prospective trials [68].

9. Expert opinion

The role of angiogenesis inhibitors in the treatment of breastcancer is continually evolving. Several of these small moleculemultitargeted tyrosine kinase inhibitors shown in Table 1

have been evaluated as monotherapy in metastatic breast can-cer. Pazopanib, as well as other similarly VEGF-targetedagents, has shown limited single-agent activity in patientswith pretreated metastatic breast cancer, as reported in severalsingle-arm Phase II studies. The results of these trials showvery little objective responses, but some disease stabilization.The 6-month clinical benefit rate of pazopanib was 25%; com-parable with that of sunitinib (16%) and sorafenib (15%), inpreviously treated metastatic breast cancer [52,69,70].Given these data, it would seem that these agents will work

best in combination with chemotherapy. However, one issueis the tolerability of administering the FDA-approved mono-therapy dose of pazopanib with cytotoxic agents. Althoughpazopanib at 800 mg could be safely combined with weeklypaclitaxel at 80 mg/m2, other regimens needed to be givenwith a lower dose of pazopanib. For example, a Phase I studyof paclitaxel with carboplatin administered every 3 weeks,determined that only 200 mg of pazopanib was feasible,because myelosuppression occurred when higher doses ofpazopanib were given [46].Sorafenib and sunitinib have each been combined with

chemotherapy in randomized trial settings in patients withmetastatic breast cancer, with sorafenib demonstratingimprovement in progression-free survival in combinationwith capecitabine (SOLTI-0701) for metastatic disease(0 -- 1 prior chemotherapy was allowed) [71]. The Phase IIItrial with sunitinib and docetaxel (SUN1064) was discontin-ued as it was unable to meet its primary end point of superiorprogression-free survival compared with docetaxel as first-line therapy. Pazopanib has not yet undergone such evalua-tion and this is needed to fully determine its potential additiveeffect to chemotherapy in the metastatic setting.Biomarkers of response and the breast cancer tumor types

for which these multitargeted VEGFR-TK inhibitors aremost sensitive to are lacking. There has been interest inusing angiogenesis inhibitors as a treatment strategy in

triple-negative breast cancer, given the lack of a targetedapproach to this breast cancer subtype. In the Phase II studyof sunitinib, the response rate in 20 patients with triple-nega-tive tumors was 15% (three PRs) [69]. Clinical responses werealso observed in a Phase II study with paclitaxel and sunitinibin which there were three responses out of nine patients withtriple-negative tumors [72]. In the Phase I study of paclitaxeland pazopanib, there were two reported partial responses inpatients with triple-negative breast cancer. These observationsare interesting, but the patient numbers are low, making theclinical significance unclear, and further clinical investigationis needed to fine-tune patient selection criteria for treatmentwith multityrosine kinase inhibitors.

The toxicity profile of pazopanib is typical of the agentsthat target VEGF or the VEGF receptors. The FDA hasestablished a black box warning for severe hepatotoxicity.Additionally, torsades de points, fatal hemorrhagic and arte-rial thrombotic events and gastrointestinal perforation havebeen reported. Given the modest activity of pazopanib andpotential life-threatening toxicities, it is essential to identifypatients who will derive the most benefit. Development ofbiomarkers either in the blood or tissue that are predictiveof response to pazopanib therapy and its toxicities is vitalto its future development. It is also essential to furtherunderstand the mechanism and risk factors of these toxicitiesto prevent it.

Pazopanib is relatively early in its clinical development forbreast cancer. The results of trials with pazopanib in combina-tion with endocrine therapy and other targeted therapy, suchas lapatinib, are awaited. Studies that combine pazopanibwith various chemotherapy agents or regimens to determinetolerability are ongoing. The role of pazopanib in the treat-ment of breast cancer will be further elucidated with theseclinical trial efforts.

Declaration of interest

L Amiri-Kordestani has no competing interests to declare.SM Swain has been a part of uncompensated advisory boardsfor Genentech (Roche), Sanofi (BiPar), Nektar and Novar-tis. She has also received funding to her institution fromBMS, Genentech (Roche), Pfizer, Novartis and Sanofi, andreceived travel expenses from Sanofi. AR Tan has receivedfunding to her institution from GSK, Eisai, Genzyme andGenentech (Roche).

Pazopanib

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Bibliography

1. Siegel R, Ward E, Brawley O, Jemal A.

Cancer statistics, 2011: the impact of

eliminating socioeconomic and racial

disparities on premature cancer deaths.

CA Cancer J Clin 2011;61:212-36

2. Chia SK, Speers CH, D’Yachkova Y,

et al. The impact of new

chemotherapeutic and hormone agents

on survival in a population-based cohort

of women with metastatic breast cancer.

Cancer 2007;110:973-9

3. Folkman J, Watson K, Ingber D,

Hanahan D. Induction of angiogenesis

during the transition from hyperplasia to

neoplasia. Nature 1989;339:58-61

4. Weidner N, Folkman J, Pozza F, et al.

Tumor angiogenesis: a new significant

and independent prognostic indicator in

early-stage breast carcinoma. J Natl

Cancer Inst 1992;84:1875-87

5. Weidner N, Semple JP, Welch WR,

Folkman J. Tumor angiogenesis and

metastasis--correlation in invasive breast

carcinoma. N Engl J Med 1991;324:1-8

6. Yoshiji H, Gomez DE, Shibuya M,

Thorgeirsson UP. Expression of vascular

endothelial growth factor, its receptor,

and other angiogenic factors in human

breast cancer. Cancer Res

1996;56:2013-16

7. Relf M, LeJeune S, Scott PA, et al.

Expression of the angiogenic factors

vascular endothelial cell growth factor,

acidic and basic fibroblast growth factor,

tumor growth factor beta-1,

platelet-derived endothelial cell growth

factor, placenta growth factor, and

pleiotrophin in human primary breast

cancer and its relation to angiogenesis.

Cancer Res 1997;57:963-9

8. Linderholm B, Grankvist K, Wilking N,

et al. Correlation of vascular endothelial

growth factor content with recurrences,

survival, and first relapse site in primary

node-positive breast carcinoma after

adjuvant treatment. J Clin Oncol

2000;18:1423-31

9. Linderholm B, Tavelin B, Grankvist K,

Henriksson R. Vascular endothelial

growth factor is of high prognostic value

in node-negative breast carcinoma.

J Clin Oncol 1998;16:3121-8

10. Gasparini G, Toi M, Gion M, et al.

Prognostic significance of vascular

endothelial growth factor protein in

node-negative breast carcinoma. J Natl

Cancer Inst 1997;89:139-47

11. Toi M, Inada K, Suzuki H,

Tominaga T. Tumor angiogenesis in

breast cancer: its importance as a

prognostic indicator and the association

with vascular endothelial growth factor

expression. Breast Cancer Res Treat

1995;36:193-204

12. Eppenberger U, Kueng W,

Schlaeppi JM, et al. Markers of

tumor angiogenesis and proteolysis

independently define high- and low-risk

subsets of node-negative breast cancer

patients. J Clin Oncol 1998;16:3129-36

13. Manders P, Beex LV, Tjan-Heijnen VC,

et al. The prognostic value of vascular

endothelial growth factor in

574 node-negative breast cancer patients

who did not receive adjuvant systemic

therapy. Br J Cancer 2002;87:772-8

14. Kerbel RS. Tumor angiogenesis. N Engl

J Med 2008;358:2039-49

15. Price DJ, Miralem T, Jiang S, et al. Role

of vascular endothelial growth factor in

the stimulation of cellular invasion and

signaling of breast cancer cells.

Cell Growth Differ 2001;12:129-35

16. Wedam SB, Low JA, Yang SX, et al.

Antiangiogenic and antitumor effects of

bevacizumab in patients with

inflammatory and locally advanced breast

cancer. J Clin Oncol 2006;24:769-77

17. Kranz A, Mattfeldt T, Waltenberger J.

Molecular mediators of tumor

angiogenesis: enhanced expression and

activation of vascular endothelial growth

factor receptor KDR in primary breast

cancer. Int J Cancer 1999;84:293-8

18. Nakopoulou L, Stefanaki K,

Panayotopoulou E, et al. Expression of

the vascular endothelial growth factor

receptor-2/Flk-1 in breast carcinomas:

correlation with proliferation.

Hum Pathol 2002;33:863-70

19. Bronzert DA, Pantazis P,

Antoniades HN, et al. Synthesis and

secretion of platelet-derived growth factor

by human breast cancer cell lines.

Proc Natl Acad Sci USA 1987;84:5763-7

20. Ginsburg E, Vonderhaar BK. Stimulation

of growth of human breast cancer cells

(T47D) by platelet derived growth

factor. Cancer Lett 1991;58:137-44

21. Carvalho S, e Silva AO, Milanezi F,

et al. c-KIT and PDGFRA in breast

phyllodes tumours: overexpression

without mutations? J Clin Pathol

2004;57:1075-9

22. Bhardwaj B, Klassen J, Cossette N, et al.

Localization of platelet-derived growth

factor beta receptor expression in the

periepithelial stroma of human breast

carcinoma. Clin Cancer Res

1996;2:773-82

23. de Jong JS, van Diest PJ,

van der Valk P, Baak JP. Expression of

growth factors, growth-inhibiting factors,

and their receptors in invasive breast

cancer. II: Correlations with proliferation

and angiogenesis. J Pathol 1998;184:53-7

24. Ariad S, Seymour L, Bezwoda WR.

Platelet-derived growth factor (PDGF) in

plasma of breast cancer patients:

correlation with stage and rate of

progression. Breast Cancer Res Treat

1991;20:11-17

25. Seymour L, Dajee D, Bezwoda WR.

Tissue platelet derived-growth factor

(PDGF) predicts for shortened survival

and treatment failure in advanced breast

cancer. Breast Cancer Res Treat

1993;26:247-52

26. Seymour L, Bezwoda WR. Positive

immunostaining for platelet derived

growth factor (PDGF) is an adverse

prognostic factor in patients with

advanced breast cancer. Breast Cancer

Res Treat 1994;32:229-33

27. Paulsson J, Sjoblom T, Micke P, et al.

Prognostic significance of stromal

platelet-derived growth factor

beta-receptor expression in human breast

cancer. Am J Pathol 2009;175:334-41

28. Llovet JM, Ricci S, Mazzaferro V, et al.

Sorafenib in advanced hepatocellular

carcinoma. N Engl J Med

2008;359:378-90

29. Escudier B, Eisen T, Stadler WM, et al.

Sorafenib in advanced clear-cell renal-cell

carcinoma. N Engl J Med

2007;356:125-34

30. Motzer RJ, Hutson TE, Tomczak P,

et al. Sunitinib versus interferon alfa in

metastatic renal-cell carcinoma. N Engl

J Med 2007;356:115-24

31. Demetri GD, van Oosterom AT,

Garrett CR, et al. Efficacy and safety of

sunitinib in patients with advanced

Amiri-Kordestani, Tan & Swain

Expert Opin. Investig. Drugs (2012) 21(2) 223

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Y

ork

Uni

vers

ity L

ibra

ries

on

08/1

1/14

For

pers

onal

use

onl

y.

gastrointestinal stromal tumour after

failure of imatinib: a randomised

controlled trial. Lancet

2006;368:1329-38

32. Raymond E, Dahan L, Raoul JL, et al.

Sunitinib malate for the treatment of

pancreatic neuroendocrine tumors.

N Engl J Med 2011;364:501-13

33. Wells SA, Robinson BG, Gagel RF, et al.

Vandetanib in locally advanced or

metastatic medullary thyroid cancer :

a randomized, double-blind phase III

trial (ZETA). J Clin Oncol

2010;28(Suppl):abstract 5503

34. Harris PA, Boloor A, Cheung M, et al.

Discovery of 5-[[4-[(2,3-dimethyl-2H-

indazol-6-yl)methylamino]-2-pyrimidinyl]

amino]-2-methyl-benzenesulfonamide

(Pazopanib), a novel and potent vascular

endothelial growth factor receptor

inhibitor. J Med Chem 2008;51:4632-40

35. Gotink KJ, Verheul HM.

Anti-angiogenic tyrosine kinase

inhibitors: what is their mechanism of

action? Angiogenesis 2010;13:1-14

36. Kumar R, Knick VB, Rudolph SK, et al.

Pharmacokinetic-pharmacodynamic

correlation from mouse to human with

pazopanib, a multikinase angiogenesis

inhibitor with potent antitumor and

antiangiogenic activity. Mol Cancer Ther

2007;6:2012-21

37. Gril B, Palmieri D, Qian Y, et al.

Pazopanib reveals a role for tumor cell

B-Raf in the prevention of HER2+ breast

cancer brain metastasis. Clin Cancer Res

2011;17:142-53

38. Hurwitz HI, Dowlati A, Saini S, et al.

Phase I trial of pazopanib in patients

with advanced cancer. Clin Cancer Res

2009;15:4220-7

39. Heath EI, Forman K, Malburg L, et al.

A phase I pharmacokinetic and safety

evaluation of oral pazopanib dosing

administered as crushed tablet or oral

suspension in patients with advanced

solid tumors. Invest New Drugs

2011 [Epub ahead of print]

40. Heath EI, Chiorean EG, Sweeney CJ,

et al. A phase I study of the

pharmacokinetic and safety profiles of

oral pazopanib with a high-fat or low-fat

meal in patients with advanced solid

tumors. Clin Pharmacol Ther

2010;88:818-23

41. Goh BC, Reddy NJ, Dandamudi UB,

et al. An evaluation of the drug

interaction potential of pazopanib, an

oral vascular endothelial growth factor

receptor tyrosine kinase inhibitor, using a

modified Cooperstown 5+1 cocktail in

patients with advanced solid tumors.

Clin Pharmacol Ther 2010;88:652-9

42. Xu CF, Reck BH, Xue Z, et al.

Pazopanib-induced hyperbilirubinemia is

associated with Gilbert’s syndrome

UGT1A1 polymorphism. Br J Cancer

2010;102:1371-7

43. Pazopanib FDA drug label

44. Sternberg CN, Davis ID, Mardiak J,

et al. Pazopanib in locally advanced or

metastatic renal cell carcinoma: results of

a randomized phase III trial.

J Clin Oncol 2010;28:1061-8

45. Tan AR, Dowlati A, Jones SF, et al.

Phase I study of pazopanib in

combination with weekly paclitaxel in

patients with advanced solid tumors.

Oncologist 2010;15:1253-61

46. Burris HA III, duBois A, Dowlati A,

et al. Pazopanib combination with

paclitaxel and carboplatin in patients

with advanced solid tumors and

gynecological cancers: results of two

phase I studies. Mol Targets Cancer Ther

2009;8(12):Supplement 1(abstract A6)

47. Study of pazopanib, paclitaxel, and

carboplatin in patients with advanced

solid tumors (NCT01407562). Available

from: http://clinicaltrials.gov/ct2/show/

NCT01407562?

term=NCT01407562&rank=1

48. Available from: http://clinicaltrials.gov

49. Dejonge M, Savage S, Verweij J, et al.

A phase I, open-label study of the safety

and pharmacokinetics (PK) of pazopanib

(P) and lapatinib (L) administered

concurrently. ASCO Annual Meeting

Proceedings Part I. J Clin Oncol

2006;24:18 Suppl 20

50. A phase I, open-label, study of pazopanib

in combination with epirubicin or

doxorubicin for advanced solid tumors

(NCT00722293). Available from:

http://clinicaltrials.gov/ct2/show/

NCT00722293?

term=NCT00722293&rank=1

51. Fasolo A, Sessa C, Bauer JA, et al.

Phase Ib clinical and pharmacological

study of multiple schedules of pazopanib

(P) and epirubicin (EPI) in patients with

advanced solid tumors. J Clin Oncol

2010;28(Suppl):abstract 3047

52. Taylor SK, Chia S, Dent S, et al.

A phase II study of pazopanib in patients

with recurrent or metastatic invasive

breast carcinoma: a trial of the Princess

Margaret Hospital phase II consortium.

Oncologist 2010;15:810-18

53. Slamon D, Gomez H, Kabbinavar F,

et al. Phase 2 study of dual VEGF/

HER2 blockade with

pazopanib + lapatinib in patients with

first-line HER2 positive advanced or

metastatic (adv/met) breast cance.

J Clin Oncol

2008;26(20 Suppl):abstract 1016

54. Slamon D, Stemmer SM, Johnston S,

et al. Phase 2 study of dual VEGF/

HER2 blockade with

pazopanib + lapatinib in patients with

first-line HER2 positive advanced or

metastatic (adv/met) breast cancer

[abstract 4114]. San Antonio: 2008

55. Rastogi P, Buyse ME, Tan AR, et al.

A phase II clinical trial of four cycles of

doxorubicin and cyclophosphamide

followed by weekly paclitaxel given

concurrently with pazopanib as

neoadjuvant therapy followed by

postoperative pazopanib for women with

locally advanced breast cancer (LABC):

A phase II trial of the NSABP

Foundation Research Group (FB-6/

VEG110264). J Clin Oncol

2010;28(Suppl):abstract TPS107

56. Miller K, Brown C, Perkins S, et al.

A pilot study of vascular endothelial

growth factor inhibition with pazopanib

in patients (pts) with lymphedema

following breast cancer treatment

[abstract P2-14-02]. San Antonio: 2010

57. Van der Auwera I, Van Laere SJ,

Van den Eynden GG, et al. Increased

angiogenesis and lymphangiogenesis in

inflammatory versus noninflammatory

breast cancer by real-time reverse

transcriptase-PCR gene expression

quantification. Clin Cancer Res

2004;10:7965-71

58. Kaufman B, Trudeau M, Awada A, et al.

Lapatinib monotherapy in patients with

HER2-overexpressing relapsed or

refractory inflammatory breast cancer:

final results and survival of the expanded

HER2+ cohort in EGF103009, a phase

II study. Lancet Oncol 2009;10:581-8

59. Study of Pazopanib Plus Lapatinib

Compared To Lapatinib Alone In

Subjects With Inflammatory Breast

Cancer (NCT00558103). Available from:

Pazopanib

224 Expert Opin. Investig. Drugs (2012) 21(2)

Exp

ert O

pin.

Inv

estig

. Dru

gs D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y Y

ork

Uni

vers

ity L

ibra

ries

on

08/1

1/14

For

pers

onal

use

onl

y.

http://clinicaltrials.gov/ct2/show/

NCT00558103?term=lapatinib

+pazopanib+breast&phase=2&rank=1

60. Eveno C, le Maignan C, Soyer P, et al.

Late anastomotic colonic dehiscence due

to antiangiogenic treatment, a specific

drug-class complication requiring specific

treatment: an example of pazopanib

complication. Clin Res

Hepatol Gastroenterol 2011;35:135-9

61. Kapadia S, Hapani S, Wu S. Risk of

high-grade liver toxicity with

pazopanib in patients with cancer:

a meta-analysis. J Clin Oncol 2011;29

(suppl; abstr 4595)

62. Xu C, Reck BH, Goodman VL, et al.

Association of the hemochromatosis

(HFE) gene with pazopanib-induced

transaminase elevations in renal cell

carcinoma. J Clin Oncol

2010;28(Suppl):abstract 3019

63. Routhouska S, Gilliam AC, Mirmirani P.

Hair depigmentation during

chemotherapy with a class III/V receptor

tyrosine kinase inhibitor. Arch Dermatol

2006;142:1477-9

64. Sideras K, Menefee ME, Burton JK,

et al. Effect of pazopanib on hair and

skin hypopigmentation: a series of three

patients. J Clin Oncol

2010;28(Suppl):abstract e13602

65. Balagula Y, Wu S, Su X, et al. The risk

of hand foot skin reaction to pazopanib,

a novel multikinase inhibitor:

a systematic review of literature and

meta-analysis. Invest New Drugs

2011 [Epub ahead of print]

66. Xu CF, Bing NX, Ball HA, et al.

Pazopanib efficacy in renal cell

carcinoma: evidence for predictive genetic

markers in angiogenesis-related and

exposure-related genes. J Clin Oncol

2011;29:2557-64

67. Nikolinakos PG, Altorki N,

Yankelevitz D, et al. Plasma cytokine and

angiogenic factor profiling identifies

markers associated with tumor shrinkage

in early-stage non-small cell lung cancer

patients treated with pazopanib.

Cancer Res 2010;70:2171-9

68. Baruchel S, Wu B, Mokhtari RB, et al.

Surrogate biomarkers of antiangiogenesis

in Children’s Oncology Group (COG)

phase I trials. J Clin Oncol

2011;29:(suppl; abstr 9502)

69. Burstein HJ, Elias AD, Rugo HS, et al.

Phase II study of sunitinib malate, an

oral multitargeted tyrosine kinase

inhibitor, in patients with metastatic

breast cancer previously treated with an

anthracycline and a taxane. J Clin Oncol

2008;26:1810-16

70. Bianchi G, Loibl S, Zamagni C, et al.

Phase II multicenter, uncontrolled trial of

sorafenib in patients with metastatic

breast cancer. Anticancer Drugs

2009;20:616-24

71. Baselga J. 15th Congress of the European

CanCer Organization (ECCO 15) and

the 34th European Society for Medical

Oncology (34th ESMO)

Multidisciplinary Congress;

23 September 2009; abstract 3LBA

72. Kozloff M, Chuang E, Starr A, et al. An

exploratory study of sunitinib plus

paclitaxel as first-line treatment for

patients with advanced breast cancer.

Ann Oncol 2010;21:1436-41

73. Available from: http://clinicaltrials.gov/

ct2/show/NCT01060514?

term=NCT01060514&rank=1

74. Available from: http://clinicaltrials.gov/

ct2/show/NCT01012362?

term=NCT01012362&rank=1

75. Available from: http://clinicaltrials.gov/

ct2/show/NCT00722293?

term=NCT00722293&rank=1

76. Available from: http://clinicaltrials.gov/

ct2/show/NCT01165385?

term=NCT01165385&rank=1

77. Available from: http://clinicaltrials.gov/

ct2/show/NCT00060151?

term=NCT00060151&rank=1

78. Available from: http://clinicaltrials.gov/

ct2/show/NCT00388076?

term=NCT00388076&rank=1

79. Available from: http://clinicaltrials.gov/

ct2/show/NCT01407562?

term=NCT01407562&rank=1

80. Available from: http://clinicaltrials.gov/

ct2/show/NCT00158782?

term=NCT00158782&rank=1

81. Available from: http://clinicaltrials.gov/

ct2/show/NCT01394211?

term=NCT01394211&rank=1

82. Available from: http://clinicaltrials.gov/

ct2/show/NCT00509587?

term=NCT00509587&rank=1

83. Available from: http://clinicaltrials.gov/

ct2/show/NCT00347919?

term=NCT00347919&rank=1

84. Available from: http://clinicaltrials.gov/

ct2/show/NCT00615524?

term=NCT00615524&rank=1

85. Available from: http://clinicaltrials.gov/

ct2/show/NCT00849472?

term=NCT00849472&rank=1

AffiliationLaleh Amiri-Kordestani1, Antoinette R Tan2 &

Sandra M Swain†3

†Author for correspondence1National Cancer Institute,

10 Center Drive, 12N226,

Bethesda, MD, USA2The Cancer Institute of New Jersey,

Medical Oncology,

195 Little Albany St,

New Brunswick, NJ, USA3Washington Cancer Institute,

MedStar Health,

Washington Hospital Center,

Washington, DC, USA

E-mail: sandra.m.swain@medstar.net

Amiri-Kordestani, Tan & Swain

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