Review

Pertuzumab in Breast Cancer:A Systematic Review

Flora Zagouri,1,2 Theodoros N. Sergentanis,3 Dimosthenis Chrysikos,3

Constantine G. Zografos,3 Martin Filipits,1 Rupert Bartsch,1

Meletios-Athanassios Dimopoulos,2 Theodora Psaltopoulou4

AbstractPertuzumab is a monoclonal antibody that represents the first among a new class of agents known as human epidermalgrowth factor receptor (HER) dimerization inhibitors. This is the first systematic review according to Preferred ReportingItems for Systematic Reviews and Meta-Analyses guidelines to synthesize all available data of pertuzumab in breastcancer. The search strategy retrieved 11 studies that evaluated pertuzumab. One study was conducted in the neo-adjuvant setting (417 patients), whereas all the others dealt with patients with recurrent, metastatic, or refractory disease(1023 patients). Six studies were conducted in HER2þ breast cancer population (1354 patients), whereas 5 studies (86patients) were conducted in HER2e (or unknown HER2 status) disease. Pertuzumab is the most recent agent approvedby the US Food and Drug Administration in combination with trastuzumab and docetaxel for the treatment of patientswith HER2þ metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastaticdisease. This approval has been based on data from a phase III Clinical Evaluation of Pertuzumab and Trastuzumab(CLEOPATRA) study. The antitumor activity with the significant reduction in the risk of progression or death, as reflectedupon the increase of 6.1 months in median progression-free survival, indicates that pertuzumab may provide an avenuefor achieving additional benefit for patients with HER2þ. Moreover, pertuzumab seems to have a putative role in themanagement of patients with HER2 who are resistant to trastuzumab. The promising role of pertuzumab in the neo-adjuvant and adjuvant settings remains to be further investigated and established in the future.

Clinical Breast Cancer, Vol. -, No. -, --- ª 2013 Elsevier Inc. All rights reserved.Keywords: Breast cancer, Perjeta, Pertuzumab, Systematic review

IntroductionThe mortality of metastatic breast cancer (MBC) remains rather

high, with an anticipated 39,620 deaths in the United States in2013, despite the continuously decreasing overall incidence andmortality rates for the disease.1 Accordingly, over the past decades,relapse rates in early breast cancer have declined steadily, mirroringsignificant improvements in systemic adjuvant treatment such as the

1Comprehensive Cancer Center Vienna, Department of Medicine I/Division ofOncology, Medical University of Vienna, Austria2Department of Clinical Therapeutics, “Alexandra” Hospital, Medical School,University of Athens, Greece3First Propaedeutic Surgical Department, Hippocrateio Hospital, University of Athens,Athens, Greece4Department of Hygiene, Epidemiology and Medical Statistics, Medical School,University of Athens, Athens, Greece

Submitted: Sep 19, 2012; Revised: May 1, 2013; Accepted: May 3, 2013

Address for correspondence: Flora Zagouri, MD, Comprehensive Cancer CenterVienna, Department of Medicine I/Division of Oncology, Medical University ofVienna, Borgschkegasse 8a, A-1090, Vienna, AustriaE-mail contact: florazagouri@yahoo.co.uk

1526-8209/$ - see frontmatter ª 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.clbc.2013.05.002

introduction of effective, molecularly targeted agents, eg, trastuzu-mab.1-3 A number of biologic agents that modulate different signaltransduction pathways are currently in clinical development, withpertuzumab being the most recent agent approved by US Food andDrug Administration (FDA); specifically, pertuzumab has recentlybeen approved (June 22, 2012) in combination with trastuzumaband docetaxel for the treatment of patients with human epidermalgrowth factor receptor 2 (HER2) positive MBC who have notreceived prior anti-HER2 therapy or chemotherapy for metastaticdisease (www.fda.gov).

Pertuzumab (2C4; Perjeta, Roche, Basel, Switzerland) is amonoclonal antibody that represents the first among a new class ofagents known as “HER dimerization inhibitors.” It binds to HER2and, subsequently, inhibits the dimerization of HER2 with otherHER receptors (HER3, HER1, and HER4), especially with HER3,reduces the percentage of heterodimers HER2-HER3, and inhibitscritical cell signaling.4-7 Worthy of note, pertuzumab, like trastu-zumab, activates antibody-dependent cellular cytotoxicity, but thepertuzumab binding site within domain II does not overlap with the

Clinical Breast Cancer Month 2013 - 1

Breast Cancer and Pertuzumab

2 - Cli

epitope on HER2 that is recognized by trastuzumab.4,8 Moreover,the mechanism of action of pertuzumab is also distinct from tyro-sine kinase inhibitors, such as gefitinib, erlotinib, or lapatinib,which bind competitively to the intracellular adenosine triphosphatebinding site of epidermal growth factor receptor and/or HER2.9

In vitro studies with tumor cell lines have shown that pertuzu-mab inhibits ligand-activated HER dimerization.7,10 Blockage ofHER2 dimerization by pertuzumab inhibits HER family down-stream signaling, eg, activation of the AKT cell survival pathway andthe mitogen-activated protein kinase pathway.11-13 Both intactpertuzumab and the Fab fragment blocked heregulin-stimulatedphosphorylation of the HER2-HER3 complex, which indicatesthat bivalency is not an absolute requirement for activity of theantibody.7 Notably, however, there seems to be synergy betweentrastuzumab and pertuzumab in high HER2-expressing breastcancer cells.13 Preclinical models have shown that pertuzumab in-hibits tumor growth in the absence of HER2þ, unlike trastuzumab,presumably by preventing ligand-stimulated HER2 heterodimerformation.7,14,15 In in vivo preclinical studies, pertuzumab has beenactive in various tumor types, including breast,7,10,15e17 ovary,16

nonesmall-cell lung carcinoma,15,17 prostate,7,18 and colon can-cer,19 whereas Agus et al7 showed dose-dependent inhibition ofxenograft tumor growth. In light of these promising nonclinicalfindings, it has been postulated that inhibition of HER2-mediateddimerization may be an effective anticancer therapy. This is thefirst systematic review of the literature to synthesize all available dataemerging from trials and to evaluate the efficacy and safety ofpertuzumab in breast cancer.

Search Strategy and Data AbstractionThis systematic review was performed in accordance with the

Preferred Reporting Items for Systematic Reviews and Meta-Analysesguidelines.20 The protocol of this systematic review was submitted tothe institutional review board of Hippocration Hospital, MedicalUniversity of Athens, Greece, and is available upon request. Eligiblearticles were identified by a search of the MEDLINE bibliographicdatabase for the period up to June 30, 2012. The search strategyincluded the following keywords: (breast and [neoplasms or neoplasmor cancer or cancers or carcinoma or carcinomas] and pertuzumab).

Language restrictions were applied (only articles in English,French, and German were considered eligible); 2 investigators (F.Z.,D.C.), working independently, searched the literature and extracteddata from each eligible study. Reviews were ineligible, whereas allprospective and retrospective studies, as well as case reports, wereeligible for this systematic review. Articles without stating the nameof the authors were excluded. Articles “epub ahead of print” whosefull text could not be found via contact with international academiclibraries, online purchase from a journal’s Web site, or contact withthe corresponding authors had to be excluded from the systematicreview. In addition, we checked all the references of relevant reviewsand eligible articles that our search retrieved so as to identifypotentially eligible conference abstracts.

All studies that examined the efficacy and safety of pertuzumab inbreast cancer and reported the relevant frequencies, regardless ofsample size, were considered eligible for this systematic review. Foreach of these studies, the following data were collected: first author,year of publication, agents, phase of the trial, number of patients

nical Breast Cancer Month 2013

treated, characteristics of patient population (first-line treatment,second-line treatment, neoadjuvant setting, etc), pathologic type(lobular, ductal, estrogen receptor [ER] status, HER2 status, etc),median age (years), overall response rate (ORR), including completeresponse rate and partial response (%), median overall survival (OS)in months, median progression-free survival (PFS) in months, andcomplications. Moreover, in the neoadjuvant setting, we includeddata regarding pathologic complete response (pCR) and overallclinical response by clinical examination (breast tumors and nodesexamined). In instances in which multiple (overlapping) publica-tions that stem from the same study were identified, the larger sizestudy was included, unless the reported outcomes were mutuallyexclusive.

ResultsThe search strategy retrieved 131 articles. Of these articles, 74

were irrelevant, 48 were reviews, one did not fulfill the inclusioncriteria,21 and 8 were finally eligible.22-29 After searching the ref-erences of all reviews and remaining articles, 3 additional conferenceabstracts and articles were also included.30-32 Overall, 11 articles(1440 patients) were eligible for the systematic review.22-32 Theaforementioned stages are illustrated in detail in Figure 1.

One study was conducted in the neoadjuvant setting (417patients),23 whereas all the others dealt with patients with recurrent,metastatic, or refractory disease (1023 patients).22,24-32 Five studiesdescribed the results of phase I trials,27-31 one of those was of aphase Ib/II trial32; 4 studies involved a phase II design,22,23,25,26 andone study was a phase III design.24 Six studies were conducted in aHER2þ breast cancer population (1354 patients),22-24,26,28,32

whereas 5 studies (86 patients) were conducted in HER2e (orunknown HER2 status) disease.25,27,29-31 Moreover, pertuzumabhas been evaluated as monotherapy,22,25,27,29 combined with tras-tuzumab,22,23,26,28 with trastuzumab-DM1,32 with trastuzumaband docetaxel,23,24 with docetaxel,23,30 and with capecitabine.31

None of the studies reported results regarding OS.22-32 Clinicaldata concerning pertuzumab have presented promising results inpatients with HER2þ MBC with an ORR that ranged between80.2% and 3.4%, whereas the median PFS ranged between 18.5and 1.5 months.22,24,26,28 On the contrary, in patients with HER2�

metastatic disease, the ORR ranged from 4.9% to 0%.25,29,31 Allstudies reported detailed outcomes that pertain to efficacy and/orsafety.22-32 Further details are provided in Tables 1-3. The quali-tative interpretation and the critical detailed evaluation of the in-dividual eligible studies are provided below, in the Discussionsection.

DiscussionHER2þ MBC

HER2þ is found in 15% to 25% of patients with breast cancerand has been shown to be a negative prognostic factor if specifictherapy is not given.33 The HER2-targeted humanized monoclonalantibody, trastuzumab, improves survival in HER2þ MBC, havingtransformed the course of the disease.34,35 However, despite thisnotable success, in most patients with HER2þ MBC, the diseaseprogresses, highlighting the need for new targeted therapies.

Pertuzumab is the most recent agent approved by the FDA incombination with trastuzumab and docetaxel for the treatment of

Figure 1 Stages of the Search Strategy

Abstracts identified and screened

131

Articles retrieved through the MEDLINE search

8

Irrelevant articles excluded

74

Reviews

48

Conference abstracts/articles retrieved as references of

relevant articles

3

Articles retrieved through the MEDLINE search + conference abstracts

11

Metastatic setting: 10 articles (1023 patients; HER2 +, 5 articles; HER2- and HER2 unknown, 5 studies)

Neoadjuvant setting: 1 article (417 patients; HER2+, 1 article)

Articles "e-pub ahead of print" whose full text could not be

found via contact with international academic

libraries, online purchase from journal's Web site, or contact

with the corresponding authors

1

Abbreviation: HER2 ¼ human epidermal growth factor receptor 2.

Flora Zagouri et al

patients with HER2þ MBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease (www.fda.gov); worthy of note, the combination of pertuzumab, trastuzu-mab, and chemotherapy is the only regimen to have shown a sig-nificant improvement in PFS compared with trastuzumab pluschemotherapy in these patients.

This approval has been based on data from a phase III ClinicalEvaluation of Pertuzumab and Trastuzumab (CLEOPATRA) studythat assessed the efficacy and safety of pertuzumab plus trastuzumabplus docetaxel compared with placebo plus trastuzumab plus doce-taxel as first-line treatment for patients with HER2þ MBC(Table 1).24 Specifically, the CLEOPATRA trial included 808 pa-tients with HER2þ MBC who were randomized to receive trastu-zumab in combination with docetaxel or pertuzumab combined withtrastuzumab and docetaxel as first-line treatment.24,36 The medianPFS was 12.4 months in the trastuzumab/docetaxel arm, whereas itwas 18.5 months in the pertuzumab/trastuzumab/docetaxel arm(hazard ratio [HR] 0.62 [95% CI, 0.51-0.75]; P < .001).24 Thesurvival data were not yet mature; of note, the interim OS analysisshowed a favorable trend for pertuzumab. As far as the safety profile

was concerned, no significant differences were noted regarding leftventricular systolic dysfunction. However, the rates of febrile neu-tropenia and grade 3/4 diarrhea were higher in the pertuzumabarm.24 The magnitude of the observed benefit compares favorablywith that of the limited options available to this group of patients,whereas with great interest are awaited the results of 3 clinical trialsthat evaluated pertuzumab in first-line therapy of HER2þ MBC.More specifically, a phase II study (VELVET) evaluated the com-bination of pertuzumab, trastuzumab, and vinorelbine,37 whereasanother phase III trial (PERUSE) examines pertuzumab in combi-nation with trastuzumab and a taxane in first-line therapy of patientswith HER2þ breast cancer (www.clinicaltrials.gov; NCT01572038).Finally, a phase II (PERTAIN) trial in postmenopausal women withHER2� and hormone receptor-positive breast cancer studies theefficacy of the combination of pertuzumab plus trastuzumab with anaromatase inhibitor as first-line therapy.38

In the metastatic setting, pertuzumab seems to play a keyrole in overcoming resistance to trastuzumab, a challenging issuein the management of patients with HER2þ breast cancer.More specifically, pertuzumab combined with trastuzumab or

Clinical Breast Cancer Month 2013 - 3

Table 1 Summary of Studies That Evaluated Pertuzumab in HER2D Metastatic Breast Cancer

Study,years

ChemotherapyRegimens

No.Patients

PatientCharacteristics(pathology) Setting

Median(range)

age, years % RR % SD PFS, mo OS, mo Phase SAEs

Cortés et al,22

2012Pertuzumab /pertuzumab þtrastuzumab

29 (17 combination) HER2þ (ERþ, 45%;ER�, 55%)

Patients with MBC whohad previouslyprogressed ontrastuzumab-basedtherapy; up to 3 priorchemotherapyregimens

55 (38-65) 3.4 (17.6) 6.9 (23.5) 1.775 (4.35) N/A II (Pertuzumab monotherapy);grade 3/4 toxicities:diarrhea (3%), fatigue(6%), oropharyngeal pain(3%), abdominal pain(3%), femur fracture (3%),ocular icterus (3%),syncope (3%);(combination treatment);grade 3/4 toxicities:diarrhea (6%), fatigue(6%), back pain (6%),pain (6%), depression(6%), osmoticdemyelination syndrome(6%)

Baselga et al,24

2012Trastuzumab þdocetaxel

406 HER2þ (HRþ, 49%;HR� 48.3%)

Patients with MBC whohad not receivedchemotherapy orbiologic therapy fortheir metastaticdisease

54 (27-89) 69.3 20.8 12.4 N/A III Grade 3/4 toxicities:neutropenia (45.8%),febrile neutropenia(7.6%), leukopenia(14.6%), diarrhea (5%),peripheral neuropathy(1.8%), anemia (3.5%),asthenia (1.5%), fatigue(3.3%), granulocytopenia(2.3%), left ventricularsystolic dysfunction(2.8%), dyspnea (2%).

Pertuzumab þtrastuzumab þdocetaxel

402 HER2þ (HRþ, 47%;HR�, 52.7%)

54 (22-82) 80.2 14.6 18.5 N/A Grade 3/4 toxicities:neutropenia (48.9%),febrile neutropenia(13.8%), leukopenia(12.3%), diarrhea (7.9%),peripheral neuropathy(2.7%), anemia (2.5%),asthenia (2.5%), fatigue(2.2%), granulocytopenia(1.5%), left ventricularsystolic dysfunction(1.2%), dyspnea (1%)

Baselga et al,26

2010Pertuzumab þtrastuzumab

66 HER2þ (ERþ, 50%;ER�, 50%)

Patients with MBC whoprogressed duringtrastuzumab (treatedwith up to 3 lines ofprior chemotherapy)

54 (25-85) 24.2 25.8 5.5 N/A II Grade 3/4 toxicities:diarrhea (3%), rash (2%),asthenia (2%), pruritus(2%)

Breast

Cancer

andPertuzum

ab

4 -ClinicalBreastCancer

Month2013

Table1

Continued

Stud

y,years

Chem

otherapy

Regimens

No.

Patients

Patient

Characteristics

(pathology)

Setting

Median

(range)

age,

years

%RR

%SD

PFS,

mo

OS,m

oPh

ase

SAEs

Portera

etal,28

2008

Pertuzumab

þtrastuzum

ab11

HER2

þ(HRþ

,27.3%;

HR�,72.7%)

MBC

,treated

with

upto

3priortrastuzum

abbasedtreatments

53(36-68)

18.2

27.3

1.5

N/A

IGrade3toxicities:

allergicreaction(9%),

leftventricular

systolic

dysfunction(9%)

Milleretal,32

2010

Trastuzumab-DM1þ

pertuzumab

23HER2

þPatientswith

locally

advanced

breast

cancer

orMBC

,who

werepreviously

treated

with

trastuzum

ab(median,

8prioragents)

N/A

39.1

N/A

N/A

N/A

Ib/II

Grade3/4toxicities:

thrombocytopenia,

pneumonia,nausea,

vomiting,diarrhea,

deafness,dyspnea

Abbreviations:ER¼

estrogenreceptor;H

ER2¼

human

epidermalgrowthfactorreceptor2;HR

¼hormonereceptors;MBC

¼metastatic

breastcancer;N

/A¼

notavailable;OS

¼overallsurvival;PFS

¼progression-freesurvival;RR

¼response

rate;SAE

¼serious

adverse

events;SD

¼stabledisease.

Flora Zagouri et al

trastuzumab-DM1 has been evaluated in 4 clinical trials in patientswho were heavily pretreated for HER2þ and who had progressed ontrastuzumab-based chemotherapy with promising results; PFSranged from 1.5 to 5.5 months, and ORR ranged from 17.6% to39.1% (Table 1).22,26,28,32 Baselga et al26 conducted a phase II trialin patients with advanced HER2þ breast cancer in whom diseaseprogression had occurred during prior trastuzumab-based therapy.26

Sixty-six patients received trastuzumab and pertuzumab until dis-ease progression or excessive toxicity.26 The ORR was 24.2%, andthe clinical benefit rate was 50%.26 The median PFS was 5.5months.26 The combination of the 2 antibodies was well tolerated,and adverse events were mild to moderate. Worthy of note, cardiacdysfunction was minimal, and no patients withdrew as a result ofcardiac-related adverse events.26 In accordance with this study,Portera et al28 conducted a phase I study of 11 patients withHER2þ who had progressed on trastuzumab-based chemotherapy,with cardiac function being closely monitored. They concluded thattrastuzumab combined with pertuzumab may have clinical benefitin selected patients who had previously been treated with trastu-zumab; however, cardiac toxicity, asymptomatic, although, in mostcases, was an issue of concern.28

Moreover, of great importance is the study conducted by Cortéset al,22 which showed that, although pertuzumab has some activityin patients with HER2þ breast cancer that progressed duringtherapy with trastuzumab, the combination of pertuzumab andtrastuzumab seems to be more active than monotherapy. In thistrial, 29 patients with HER2þ breast cancer whose disease pro-gressed during prior trastuzumab-based therapy received pertuzu-mab until progressive disease or unacceptable toxicity, whereas 17patients with disease progression continued to receive pertuzumabwith the addition of trastuzumab.22 The ORR and the clinicalbenefit rate were 3.4% and 10.3%, respectively, during pertuzumabmonotherapy, whereas, with the addition of trastuzumab, the ORRand the clinical benefit rate were 17.6% and 41.2%, respectively.22

Moreover, PFS was longer with combination therapy than withpertuzumab monotherapy (17.4 vs. 7.1 weeks, respectively).22

Finally, very encouraging seems to be the data coming from aphase Ib/II trial that evaluated the combination of pertuzumab andtrastuzumab-DM1.32 Safety, tolerability, and preliminary efficacy(ORR, 39.1%) of the combination are really promising, with nosubstantial increase in toxicity over single agents. Given the resultsof this trial, a phase III (MARIANNE) trial is currently conducted.The MARIANNE trial evaluates trastuzumab-DM1 with orwithout pertuzumab compared with trastuzumab plus taxane forfirst-line treatment of HER2þ, progressive or recurrent locallyadvanced or MBC (www.clinicaltrials.gov; NCT01120184). Thissystemic chemotherapy-sparing combination has the potential toestablish a new treatment paradigm by optimizing efficacy whileminimizing toxicity.

Analysis of these findings suggests that targeting HER2þ tumorswith 2 anti-HER2 monoclonal antibodies that have complementarymechanisms of action results in a more comprehensive blockade ofHER2 and highlights the clinical importance of preventing theligand-dependent formation of HER2 dimers to silence HER2signaling to the greatest extent possible. Therefore, the promisingantitumor activity with the significant reduction in the risk ofprogression or death and an increase in median PFS further suggest

Clinical Breast Cancer Month 2013 - 5

Table 2 Summary of Studies That Evaluated Pertuzumab in HER2e (or Unknown HER2 Status) Metastatic Breast Cancer

Study, yearsChemotherapy

regimensNo.

Patients

PatientCharacteristics(pathology) Setting

Median(range)

age, years % RR % SD PFS, mo OS, mo Phase SAEs

Agus et al, 29

2005Pertuzumab 3 Not specified Patients with incurable, locally

advanced, recurrent, or MBC, whohad progressed during or afterstandard therapy

N/A 0 0 N/A N/A I N/A

Yamamoto et al,27 2009

Pertuzumab 1 HER2� MBC refractory to standard therapy N/A N/A N/A N/A N/A I N/A

Gianni et al, 25

2010Pertuzumab 420 mg(load 840 mg) q3w

41 HER2� MBC, treated with up to 2 linesof chemotherapy, and hadanthracycline-containing therapyeither in an adjuvant setting or formetastatic disease

54 (33-76) 4.9 43.9 1.525 N/A II Grade 3/4 toxicities:diarrhea (7.3%),fatigue/asthenia(2.4%), vomiting(2.4%)

Pertuzumab1050 mg q3w

37 55 (36-78) 0 37.8 1.525 N/A Grade 3/4 toxicities:diarrhea (5.4%)

Attard et al, 30

2007Pertuzumab þdocetaxel

1 Not specified Patients with MBC who had hadprogressed during or after standardtherapy or for whom no standardtherapy was available

N/A N/A N/A N/A N/A Ib N/A

Albanell et al,31

2008Pertuzumab þcapecitabine

3 HER2� Patients with MBC for whom nostandard therapy was available

N/A 0 66.7 N/A N/A I N/A

Abbreviations: HER ¼ human epidermal growth factor receptor; MBC ¼ metastatic breast cancer; N/A ¼ not available; OS ¼ overall survival; PFS ¼ progression-free survival; q3w ¼ every 3 weeks; RR ¼ response rate; SAE ¼ serious adverse event; SD ¼ stable disease.

Breast

Cancer

andPertuzum

ab

6 -ClinicalBreastCancer

Month2013

Table 3 Summary of Studies that Evaluated Pertuzumab in the Neoadjuvant Setting

Study,years

Chemotherapyregimens

No.Patients

PatientCharacteristics(pathology) Setting

Median(range)

Age, years % pCR% Clinicalresponsea PFS, mo OS, mo Phase SAEs

Gianniet al,23

2012

Trastuzumab þdocetaxel

107 HER2þ

(HRþ, 47%; HR�,53%)

Neoadjuvant setting(operable [T2, 3N0, 1, M0],locally advanced [T2,3N2, 3M0, or T4aecNxM0],or inflammatory [T4dNx M0]breast cancer with primarytumors larger than 2 cmin diameter)

50 (32-74) 29.0 81.4 N/A N/A II Grade 3-5 toxicities:neutropenia (57%), febrileneutropenia (7%), leukopenia(12%), diarrhea (4%),granulocytopenia (1%), rash(2%), menstruation irregular(1%), ALT increased (3%),pyrexia (1%), other (7%)

Pertuzumab þtrastuzumab þdocetaxel

107 HER2þ(HRþ: 47%; HR�:53%)

50 (28-77) 45.8 88 N/A N/A Grade 3-5 toxicities:neutropenia (45%), febrileneutropenia (8%), leukopenia(5%), diarrhea (6%), asthenia(2%), granulocytopenia (1%),rash (2%), menstruationirregular (1%), drughypersensitivity (1%), pyrexia(1%), fulminant hepatitis(1%), other (2%), deaths (1%)

Pertuzumab þtrastuzumab

107 HER2þ

(HRþ, 48%; HR�,52%)

49 (22-80) 16.8 66.3 N/A N/A Grade 3-5 toxicities:neutropenia (1%), drughypersensitivity (2%),congestive heart failure (1%),other (3%)

Pertuzumab þdocetaxel

96 HER2þ

(HRþ, 48%; HR�,52%)

49 (27-70) 24.0 73.9 N/A N/A Grade 3-5 toxicities:neutropenia (55%), febrileneutropenia (7%),leukopenia (7%), diarrhea(4%), asthenia (2%),granulocytopenia (2%), rash(1%), menstruation irregular(4%), ALT increased (1%),other (3%), deaths (1%)

Abbreviations: ALT ¼ alanine transaminase; HER2 ¼ human epidermal growth factor receptor 2; HR ¼ hormone receptors; N/A ¼ not available; OS ¼ overall survival; pCR ¼ pathologic complete response; PFS ¼ progression-free survival; SAE ¼ serious adverse event.aBy clinical examination (breast tumors and nodes examined).

FloraZagouri

etal

ClinicalBreastCancerMonth

2013 -7

Breast Cancer and Pertuzumab

8 - Cli

that pertuzumab may provide an avenue for achieving long-lastingbenefit from trastuzumab-based therapy in patients with HER2þ.

HER2� MBCIn preclinical studies, pertuzumab was also proven effective in

HER2� tumors, probably by preventing the formation of ligand-stimulated HER2 heterodimers.7,14,15 Hence, 4 phase I trials27,29-31

and one phase II25 trial were conducted in patients with HER2�

breast cancer (or unknown HER2 status), without promising results(ORR, 0%- 4.9%; stable disease, 0-66.7%; PFS, 1.525 months,Table 2). Given the data in preclinical studies, it seems that the roleof pertuzumab in the treatment of HER2� MBC, if any, remains tobe clarified in the future. However, studies are additionally war-ranted to evaluate its potential role in this subtype of breast cancerin which biomarker analysis seems mandatory to further optimizepatient selection.

Neoadjuvant SettingIn the neoadjuvant setting, pertuzumab has been evaluated with

promising results in a phase II (NeoSphere) trial (Table 3).23 In thismulticenter, open-label, phase II study, treatment-naive women withHER2þ breast cancer were randomly assigned to receive 4 cycles oftrastuzumab plus docetaxel or pertuzumab, trastuzumab and doce-taxel or pertuzumab and trastuzumab or pertuzumab plus doce-taxel,23,39 Patients given the triple combination of pertuzumab,trastuzumab, and docetaxel had a significantly improved pCRrate (45.8% [95% CI, 36.1%-55.7%]) compared with thosegiven trastuzumab plus docetaxel (29.0% [95% CI, 20.6%-38.5%]),those given pertuzumab plus docetaxel (24% [95% CI, 15.8%-33.7%]) or pertuzumab and trastuzumab (16.8% [95% CI, 10.3%-25.3%]) given pertuzumab and trastuzumab.23 The combination ofthe 3 agents was well tolerated with neutropenia (45%), febrileneutropenia (8%), diarrhea (6%), and leukopenia (5%) being themost common grade 3/4 adverse events.23 Of note, no increase incardiac risk was observed with the addition of pertuzumab to theother regimens (Table 3). Although the combination of pertuzumabplus docetaxel was efficacious, the combination of chemotherapywith both antibodies was more active than chemotherapy with eitherantibody alone. Thus, this triplet combination could be an attractiveproposition for patients with HER2þ breast cancer.

Additional studies in the neoadjuvant setting, ie, NeoadjuvantLapatinib and/or Trastuzumab Treatment Optimisation,40 havealso confirmed the potential of dual HER2-targeted therapy. Takentogether, these results suggest that different mechanisms of action ofHER2-targeting drugs could provide a more comprehensiveblockade of the signaling pathway when combined. Moreover,NeoSphere also examined a chemotherapy-free regimen of pertu-zumab and trastuzumab that resulted in pCRs in a proportion ofwomen and a favorable safety profile.23 These findings suggest apotential future role for chemotherapy-free HER2-targeted therapy,although such regimens require further clinical investigation and theassessment of predictive biomarkers.

In the neoadjuvant setting, pertuzumab is currently being eval-uated in another phase II trial Trastuzumab plus Pertuzumab inNeoadjuvant HER2-Positive Breast Cancer (TRYPHAENA) (www.clinicaltrials.gov; NCT00976989). In the TRYPHAENA study,pertuzumab and trastuzumab are being administered either

nical Breast Cancer Month 2013

sequentially or concurrently with an anthracycline-containing orconcurrently with an anthracycline-free standard regimen to estab-lish the tolerability profile of these regimens in patients withHER2þ breast cancer.41

Adjuvant SettingGiven the significant antitumor activity, the safe toxicity profile,

and the promising results that pertuzumab yielded in the metastaticand the neoadjuvant setting, Pertuzumab is currently under evalua-tion in the adjuvant setting (www.clinicaltrials.gov; NCT01358877).This randomized, double-blind, placebo-controlled, 2-arm study(APHINITY) will assess the safety and efficacy of pertuzumab inaddition to chemotherapy plus trastuzumab in patients with operableHER2þ primary breast cancer. After surgery, patients are randomizedto receive either pertuzumab or placebo every 3 weeks for 1 year, inaddition to 6-8 cycles of chemotherapy and 1 year of trastuzumab.The results of this trial are awaited with interest.

Adverse Events: Special Issues for ConsiderationWhen taking into consideration the data that evaluated pertu-

zumab in more than 1400 patients with breast cancer enrolled intoclinical trials, it seems that the agent is safe and well tolerated, withdiarrhea, nausea and/or vomiting, asthenia, and rash being the mostfrequent related toxicities (mostly grade 1-2). Moreover, specialconsideration should be given to cardiotoxicity.

Cardiotoxicity. HER2 and HER4, besides their essential role in cellgrowth and survival, are also important for homeostatic mechanismsin the cardiac myocyte.42 HER signaling is also thought to play animportant role in the sympathovagal control systems of the heart.43 Inpreclinical studies, it has been found that HER2 and HER4 are crucialfor mouse embryonic heart development.44 Furthermore, in adult ratmyocardium, neuregulin signaling through HER2:HER4 hetero-dimers mediates synthesis and stabilization of myocardial structuralproteins and attenuates myocyte death.45 Therefore, there is justifiedconcern regarding the possibility of undesirable effects of pertuzumabon the heart. Data from a recent meta-analysis of cardiac safety inpatients with cancer show that patients treated with pertuzumabexperienced relatively low levels of asymptomatic left ventricular sys-tolic dysfunction or symptomatic heart failure.46 Furthermore, therewas no notable increase in cardiac adverse effects when pertuzumabwas given in combination with other anticancer agents, eg, trastuzu-mab.46 More specifically, 6.9%, 3.4%, and 6.5% of the patientstreated with pertuzumab alone or with pertuzumab in combinationwith a noneanthracycline-containing cytotoxic, or with trastuzumab,respectively, developed asymptomatic left ventricular systolicdysfunction.46 In addition, 0.3%, 1.1%, and 1.1%, of the patientstreated with pertuzumab alone, with pertuzumab in combination witha noneanthracycline-containing cytotoxic, or with trastuzumab,respectively, displayed symptomatic heart failure.46 Nonetheless, it isnecessary that cardiac risk factors be taken into account when makinga decision regarding treatment with pertuzumab.

Diarrhea. Diarrhea was the only significant finding in standardtoxicology studies conducted in rodent and primate models.47

Diarrhea as an adverse event has been correlated to HER1(epidermal growth factor receptor) inhibition and clinical efficacy.48

Flora Zagouri et al

Therefore, the increase in diarrhea seen with pertuzumab could beindicative of disruption of HER1:HER2 heterodimer signaling bythe agent. The incidence of all-grade diarrhea ranged between 27%and 72% in different studies, whereas the incidence of grade 3/4diarrhea ranged between 3% and 7.9% (Tables 1-3).22-32 Therefore,diarrhea was mainly grade 1 or 2, was manageable and usuallyresolved without sequelae. Dose reduction or treatment interruptionrarely was needed.22-32

Nausea and/or Vomiting. Nausea and vomiting were commonadverse events, with an incidence of all-grade events, which rangedfrom 11% to 67%; however, most of them were grades 1 and 2,with grade 3/4 adverse event varying between 0% and 2.4%.22-32

Asthenia. The incidence of all-grade asthenia with pertuzumabranged between 3% and 62% along with the clinical trials, whereasgrade 3/4 asthenia varied between 0% and 2.5%.22-32

Skin Rash. Skin rash is reported as a common pertuzumab-relatedadverse event in most clinical trials, probably related to its mecha-nism of action, albeit at varying frequencies (reviewed in Druckeret al49). The rash was generally reported as low-grade (grades 1-2)and had a papulopustular (acneiform) phenotype, similar to thatseen with other epidermal growth factor receptor and HER2 tar-geting agents.49 According to the recently published meta-analysis,the risk of skin rash varied along with different tumor typeswith patients with breast cancer who exhibited higher incidence ofrash.49 The incidence of all-grade and high-grade rash with pertu-zumab was 24.6% (95% CI, 19.3%-30.8%) and 1.1% (95% CI,0.5%-2.2%), respectively.49 However, despite the fact that rashtoxicity is usually mild to moderate, patients are often treated forextended periods of time, which makes this nonsevere adverse eventless tolerable.50 Therefore, early recognition and appropriate treat-ment of the rash may increase patient quality of life and adherenceto therapy, which would in turn improve oncologic outcome.

Conclusion and FuturePerspectives

The antitumor activity with the significant reduction in the riskof progression or death, as reflected upon the increase of 6.1 monthsin median PFS, indicates that pertuzumab may provide an avenuefor achieving additional benefit for patients with HER2þ. Therecent approval of pertuzumab by the FDA may indeed mark a newera in the treatment of patients with HER2þ MBC. Pertuzumab isthe most recent agent approved by FDA in combination withtrastuzumab and docetaxel for the treatment of patients withHER2þ MBC and who have not received prior anti-HER2 therapyor chemotherapy for metastatic disease. This approval has beenbased on data from a phase III (CLEOPATRA) study. Moreover,pertuzumab seems to have a putative role in the management ofpatients with HER2 resistant to trastuzumab. The promising role ofpertuzumab in the neoadjuvant and adjuvant settings remains to befurther investigated and established in the future.

AcknowledgementsF. Zagouri is receiving a research grant from Hellenic Society of

Medical Oncologists.

DisclosureThe authors have stated that they have no conflicts of interest.

References1. American Cancer Society. Cancer Facts and Figures 2012. Atlanta: American

Cancer Society, Available at, http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-key-statistics. Accessed May 21, 2013.

2. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plusadjuvant chemotherapy for operable human epidermal growth factor receptor2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABPB-31. J Clin Oncol 2011; 29:3366-73.

3. Morris SR, Carey LA. Trastuzumab and beyond: new possibilities for thetreatment of HER2-positive breast cancer. Oncology (Williston Park) 2006; 20:1763-76.

4. Cho HS, Mason K, Ramyar KX, et al. Structure of the extracellular region ofHER2 alone and in complex with the Herceptin Fab. Nature 2003; 421:756-60.

5. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev MolCell Biol 2001; 2:127-37.

6. Harari D, Yarden Y. Molecular mechanisms underlying ErbB2/HER2 action inbreast cancer. Oncogene 2000; 19:6102-14.

7. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated ErbB2 signalinginhibits breast and prostate tumor growth. Cancer Cell 2002; 2:127-37.

8. Fendly BM, Winget M, Hudziak RM, et al. Characterization of murine mono-clonal antibodies reactive to either the human epidermal growth factor receptor orHER2/neu gene product. Cancer Res 1990; 50:1550-8.

9. Arteaga CL. ErbB-targeted therapeutic approaches in human cancer. Exp Cell Res2003; 284:122-30.

10. Schaefer G, Fitzpatrick VD, Sliwkowski MX. Gamma-heregulin: a novel heregulinisoform that is an autocrine growth factor for the human breast cancer cell line,MDA-MB-175. Oncogene 1997; 15:1385-94.

11. Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from thestructure of the ErbB2-pertuzumab complex. Cancer Cell 2004; 5:317-28.

12. Badache A, Hynes NE. A new therapeutic antibody masks ErbB2 to its partners.Cancer Cell 2004; 5:299-301.

13. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab andpertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res2004; 64:2343-6.

14. Agus DB, Akita RW, Fox WD, et al. A potential role for activated HER-2 inprostate cancer. Semin Oncol 2000; 27:76-83, discussion 92-100.

15. Malik M, Totpal K, Balter I. Dose response studies of recombinant humanizedmonoclonal antibody 2C4 (pertuzumab) in tumor xenograft models. Proc Am AssocCancer Res 2003; 44:773.

16. Lewis GD, Lofgren JA, McMurtrey AE, et al. Growth regulation of human breastand ovarian tumor cells by heregulin: evidence for the requirement of ErbB2 as acritical component in mediating heregulin responsiveness. Cancer Res 1996; 56:1457-65.

17. Friess T, Bauer S, Burger AM. In vivo activity of recombinant humanisedmonoclonal antibody 2C4 in xenografts is independent of tumour type and degreeof HER-2 overexpression. EORTC-NCI-AACR Conference, Frankfurt, Germany:2002; abstract 953.

18. Mendoza N, Phillips GL, Silva J, et al. Inhibition of ligand-mediated HER2activation in androgen-independent prostate cancer. Cancer Res 2002; 62:5485-8.

19. Mann M, Sheng H, Shao J, et al. Targeting cyclooxygenase 2 and HER-2/neupathways inhibits colorectal carcinoma growth. Gastroenterology 2001; 120:1713-9.

20. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reportingsystematic reviews and meta-analyses of studies that evaluate health care in-terventions: explanation and elaboration. J Clin Epidemiol 2009; 62:e1-34.

21. Lu D, Burris HA 3rd, Wang B, et al. Drug interaction potential of trastuzumabemtansine combined with pertuzumab in patients with HER2-positive metastaticbreast cancer. Curr Drug Metab 2012; 13:911-22.

22. Cortés J, Fumoleau P, Bianchi GV, et al. Pertuzumab monotherapy aftertrastuzumab-based treatment and subsequent reintroduction of trastuzumab: ac-tivity and tolerability in patients with advanced human epidermal growth factorreceptor 2-positive breast cancer. J Clin Oncol 2012; 30:1594-600.

23. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant per-tuzumab and trastuzumab in women with locally advanced, inflammatory, or earlyHER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label,phase 2 trial. Lancet Oncol 2012; 13:25-32.

24. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel formetastatic breast cancer. N Engl J Med 2012; 366:109-19.

25. Gianni L, Lladó A, Bianchi G, et al. Open-label, phase II, multicenter, randomizedstudy of the efficacy and safety of two dose levels of pertuzumab, a humanepidermal growth factor receptor 2 dimerization inhibitor, in patients with humanepidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol2010; 28:1131-7.

26. Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastu-zumab in patients with human epidermal growth factor receptor 2-positive met-astatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol2010; 28:1138-44.

27. Yamamoto N, Yamada Y, Fujiwara Y, et al. Phase I and pharmacokinetic study ofHER2-targeted rhuMAb 2C4 (pertuzumab, RO4368451) in Japanese patientswith solid tumors. Jpn J Clin Oncol 2009; 39:260-6.

Clinical Breast Cancer Month 2013 - 9

Breast Cancer and Pertuzumab

10 -

28. Portera CC, Walshe JM, Rosing DR, et al. Cardiac toxicity and efficacy of tras-tuzumab combined with pertuzumab in patients with [corrected] humanepidermal growth factor receptor 2-positive metastatic breast cancer. Clin CancerRes 2008; 14:2710-6.

29. Agus DB, Gordon MS, Taylor C, et al. Phase I clinical study of pertuzumab, anovel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol2005; 23:2534-43.

30. Attard G, Kitzen J, Blagden SP, et al. A phase Ib study of pertuzumab, a re-combinant humanised antibody to HER2, and docetaxel in patients with advancedsolid tumours. Br J Cancer 2007; 97:1338-43.

31. Albanell J, Montagut C, Jones ET, et al. A phase I study of the safety and phar-macokinetics of the combination of pertuzumab (rhuMab 2C4) and capecitabinein patients with advanced solid tumors. Clin Cancer Res 2008; 14:2726-31.

32. Miller K, Gianni L, Andre F, et al. A phase Ib/II trial of trastuzumab-DM1(T-DM1) with pertuzumab (P) for women with HER2-positive, locallyadvanced or metastatic breast cancer (BC) who were previously treated withtrastuzumab (T). J Clin Oncol 2010; 28 (15s):abstract 1012.

33. Dawood S, Broglio K, Buzdar AU, et al. Prognosis of women with metastaticbreast cancer by HER2 status and trastuzumab treatment: an institutional-basedreview. J Clin Oncol 2010; 28:92-8.

34. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a mono-clonal antibody against HER2 for metastatic breast cancer that overexpressesHER2. N Engl J Med 2001; 344:783-92.

35. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the ef-ficacy and safety of trastuzumab combined with docetaxel in patients with humanepidermal growth factor receptor 2-positive metastatic breast cancer administeredas first-line treatment: the M77001 study group. J Clin Oncol 2005; 23:4265-74.

36. Baselga J, Swain SM. CLEOPATRA: a phase III evaluation of pertuzumab andtrastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer 2010;10:489-91.

37. Perez EA, Lopez-Vega JM, Del Mastro L, et al. A combination of pertuzumab,trastuzumab, and vinorelbine for first-line treatment of patients with HER2-positive metastatic breast cancer: an open-label, two-cohort, phase II study(VELVET). J Clin Oncol 2012, 30s:abstract TPS653.

38. Rimawi MF, Poole CJ, Ferrero JM, et al. Pertuzumab in combination with tras-tuzumab plus an aromatase inhibitor in patients with hormone receptor-positive,

Clinical Breast Cancer Month 2013

HER2-positive metastatic breast cancer: a randomized phase II study(PERTAIN). J Clin Oncol 2012, 30s:abstract TPS654.

39. Walshe JM, Denduluri N, Berman AW, et al. A phase II trial with trastuzumaband pertuzumab in patients with HER2-overexpressed locally advanced and met-astatic breast cancer. Clin Breast Cancer 2006; 6:535-9.

40. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre,phase 3 trial. Lancet 2012; 379:633-40.

41. Schneeweiss A, Chia S, Hickish T, et al. Neoadjuvant pertuzumab and trastuzu-mab concurrent or sequential with an anthracycline-containing or concurrentwith an anthracycline-free standard regimen: a randomized phase II study(TRYPHAENA). Cancer Res 2011; 71:112s.

42. De Keulenaer GW, Doggen K, Lemmens K. The vulnerability of the heart as apluricellular paracrine organ: lessons from unexpected triggers of heart failure intargeted ErbB2 anticancer therapy. Circ Res 2010; 106:35-46.

43. Okoshi K, Nakayama M, Yan X, et al. Neuregulins regulate cardiacparasympathetic activity: muscarinic modulation of beta-adrenergic activity inmyocytes from mice with neuregulin-1 gene deletion. Circulation 2004; 110:713-7.

44. Gassmann M, Casagranda F, Orioli D, et al. Aberrant neural and cardiac devel-opment in mice lacking the ErbB4 neuregulin receptor. Nature 1995; 378:390-4.

45. Zhao YY, Sawyer DR, Baliga RR, et al. Neuregulins promote survival and growthof cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal andadult ventricular myocytes. J Biol Chem 1998; 273:10261-9.

46. Lenihan D, Suter T, Brammer M, et al. Pooled analysis of cardiac safety in patientswith cancer treated with pertuzumab. Ann Oncol 2012; 23:791-800.

47. Towndrow KM, Dybdal N, Nguyen LT, et al. Effects of chronic pertuzumab-mediated HER2 pathway inhibition. Society of Toxicology, Baltimore, MD:March 21-25, 2004, abstract 76.

48. Rich JN, Rasheed BK, Yan H. EGFR mutations and sensitivity to gefitinib. N EnglJ Med 2004; 351:1260-1.

49. Drucker AM, Wu S, Dang CT, et al. Risk of rash with the anti-HER2 dimer-ization antibody pertuzumab: a meta-analysis. Breast Cancer Res Treat 2012; 135:347-54.

50. Edgerly M, Fojo T. Is there room for improvement in adverse event reporting inthe era of targeted therapies? J Natl Cancer Inst 2008; 100:240-2.