Johnston. EGF30008. Tykerb With Letrozole

Lapatinib Combined With Letrozole Versus Letrozole andPlacebo As First-Line Therapy for PostmenopausalHormone Receptor–Positive Metastatic Breast CancerStephen Johnston, John Pippen Jr, Xavier Pivot, Mikhail Lichinitser, Saeed Sadeghi, Veronique Dieras,Henry Leonidas Gomez, Gilles Romieu, Alexey Manikhas, M. John Kennedy, Michael F. Press, Julie Maltzman,Allison Florance, Lisa O’Rourke, Cristina Oliva, Steven Stein, and Mark PegramFrom the Royal Marsden Hospital,

London; GlaxoSmithKline, Middlesex,United Kingdom; Sammons CancerCenter, Dallas, TX; David Geffen Schoolof Medicine; University of SouthernCalifornia/Norris ComprehensiveCancer Center, Los Angeles, CA;GlaxoSmithKline, Collegeville, PA;GlaxoSmithKline, Durham, NC; Univer-sity of Miami Sylvester ComprehensiveCancer Center, Miami, FL; UniversityHospital J. Minjoz, L’Institut National dela Sante et de la Recherche MedicaleUnit 645, Besancon; Institut Curie,Paris; Department of Medical Oncology,CRLC Val d’Aurelle, Montpellier,France; Cancer Research Center,Moscow; City Clinical Oncology Dispen-sary, St Petersburg, Russia; InstitutoDe Enfermedades Neoplasicas, Lima,Peru; and The All-Ireland CooperativeOncology Research Group, Dublin,Ireland.

Submitted April 16, 2009; acceptedJune 25, 2009; published online aheadof print at www.jco.org on September28, 2009.

Supported by GlaxoSmithKline and byNational Health Service funding to theRoyal Marsden National Institute forHealth Research Biomedical ResearchCentre.

Presented in part at the 31st AnnualSan Antonio Breast Cancer Sympo-sium, December 10-14, 2008, SanAntonio, TX.

Authors’ disclosures of potential con-flicts of interest and author contribu-tions are found at the end of thisarticle.

Clinical Trials repository link available onJCO.org.

Corresponding author: StephenJohnston, MA, PhD, FRCP, Royal Mars-den National Health Service FoundationTrust & Institute of Cancer Research,Fulham Rd, Chelsea, London, SW3 6JJ,United Kingdom; e-mail: [email protected].

© 2009 by American Society of ClinicalOncology

0732-183X/09/2799-1/$20.00

DOI: 10.1200/JCO.2009.23.3734

A B S T R A C T

PurposeCross-talk between human epidermal growth factor receptors and hormone receptor pathwaysmay cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib,a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermalgrowth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment ofhormone receptor (HR) –positive metastatic breast cancer (MBC).

Patients and MethodsPostmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mgorally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point wasprogression-free survival (PFS) in the HER2-positive population.

ResultsIn HR-positive, HER2-positive patients (n � 219), addition of lapatinib to letrozole significantlyreduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] � 0.71; 95% CI,0.53 to 0.96; P � .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit(responsive or stable disease � 6 months) was significantly greater for lapatinib-letrozole versusletrozole-placebo (48% v 29%, respectively; odds ratio [OR] � 0.4; 95% CI, 0.2 to 0.8; P � .003).Patients with centrally confirmed HR-positive, HER2-negative tumors (n � 952) had no improve-ment in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as asignificant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS forlapatinib-letrozole was seen in patients who experienced relapse less than 6 months since priortamoxifen discontinuation (HR � 0.78; 95% CI, 0.57 to 1.07; P � .117). Grade 3 or 4 adverseevents were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea,10% v 1%; rash, 1% v 0%, respectively), but they were manageable.

ConclusionThis trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantlyenhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

J Clin Oncol 27. © 2009 by American Society of Clinical Oncology

INTRODUCTION

Despite recent advances in the treatment of hor-mone receptor (HR)–positive metastatic breast cancer(MBC), resistance to endocrine therapies limits theirsuccess. Cross-talk between pathways involving theepidermal growth factor family of receptors—ErbB1 (epidermal growth factor receptor [EGFR])and ErbB2 (human epidermal growth factor recep-tor 2 [HER2])—and the estrogen receptor (ER)has been implicated in resistance to endocrinetherapy.1-5 This has created a rationale for usingtargeted agents against EGFR pathways in combina-

tion with endocrine manipulation to overcome en-docrine resistance.

Overexpression of HER2 confers resistanceto established endocrine therapies,2,6-8 and a ran-domized trial in HR-positive, HER2-positiveMBC reported that trastuzumab combined withthe aromatase inhibitor (AI) anastrozole doubledthe median progression-free survival (PFS) com-pared with anastrozole alone from 2.4 to 4.8months.9 Experimental models have shown thathormone-sensitive ER-positive breast cancer cellsthat initially lack EGFR or HER2 develop acquiredresistance over time with enhanced expression of

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receptors involved in cross-talk with ER.10-14 Two randomized trials inHR-positive MBC suggested that the EGFR tyrosine kinase inhibitor(TKI) gefitinib may improve PFS when added to endocrine thera-py.15,16 Thus, for patients with HR-positive, HER2-positive tumors, astrategy of combined therapy might enhance endocrine effectiveness,whereas it could delay disease progression for those with HR-positive,HER2-negative tumors at risk of early relapse.

Lapatinib, a potent, orally active, dual TKI against EGFR andHER2, has demonstrated activity in both trastuzumab-naïve andpretreated HER2-positive MBC.17-25 Synergy between lapatiniband tamoxifen occurs in models of endocrine resistance.26,27 A phaseI study confirmed that letrozole and lapatinib could be coadminis-tered at their recommended doses without pharmacokinetic interac-tion.28 This phase III trial compared the combination of letrozole pluslapatinib with letrozole plus placebo as first-line treatment of patients

with HR-positive MBC, including a population with known HER2-positive tumors.

PATIENTS AND METHODS

Patients

Eligible patients were postmenopausal women with histologically con-firmed stage IIIB/IIIC or IV ER-positive and/or progesterone receptor (PgR)–positive invasive breast cancer. No prior therapy for advanced or metastaticdisease was allowed. Prior neoadjuvant/adjuvant antiestrogen therapy wasallowed, as was adjuvant AI and/or trastuzumab, provided it was completedmore than 1 year before study entry. All patients had an Eastern CooperativeOncology Group performance status of 0 or 1, normal organ function, and aleft ventricular ejection fraction (LVEF) within the institutional range of nor-mal. Patients with extensive symptomatic visceral disease were excluded.

Table 1. Baseline Patient Demographics and Clinical Characteristics

Demographic or Clinical Characteristic

HER2 Positive ITT

Letrozole � Placebo(n � 108)

Letrozole � Lapatinib(n � 111)

Letrozole � Placebo(n � 644)

Letrozole � Lapatinib(n � 642)

No. of Patients % No. of Patients % No. of Patients % No. of Patients %

Age, years�

Median 59 60 63 62Range 45-87 44-85 35-95 31-94

ECOG performance status�

0 51 47 59 53 349 54 370 58� 1 57 53 51 46 286 44 268 42

Hormone receptor status�

ER/PgR positive 69 64 74 67 414 64 420 65ER positive/PgR negative 20 19 19 17 90 14 91 14

Disease stageIIIB or IIIC 7 6 5 5 30 5 25 4IV 101 94 106 95 613 95 616 96

No. of metastatic sites�

Median 2 2 2 2Range 1-7 1-7 0-7 0-7

Disease stageBone only 18 17 16 14 85 13 94 15Visceral or soft tissue 90 83 95 86 559 87 548 85Liver 37 34 33 30 171 27 146 23Lung 40 37 43 39 242 38 248 39Lymph node 43 40 57 51 304 47 312 49Soft tissue 31 29 35 32 218 34 212 33Other 18 17 19 17 127 20 125 19

Previous therapyEndocrine� 62 57 60 54 317 49 313 49Tamoxifen or toremifene only 60 56 59 53 302 47 300 47Aromatase inhibitor only 1 � 1 1 � 1 3 � 1 5 � 1Chemotherapy� 51 47 61 55 280 43 281 44Anthracycline only 38 35 41 37 172 27 171 27Anthracyclines and taxanes 9 8 9 8 41 6 42 7Other 4 4 11 10 66 10 68 11Biologic therapy (any) 1 � 1 1 � 1 1 � 1 2 � 1

Interval since prior adjuvant antiestrogen therapy�

� 6 months or no prior therapy 67 62 73 66 487 76 501 78� 6 months 41 38 38 34 157 24 141 22

Abbreviations: HER2, human epidermal growth factor receptor 2; ITT, intent to treat; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; PgR,progesterone receptor.

�Indicates prespecified baseline prognostic factors used in predefined stepwise Cox regression model. Additional factors included treatment, disease-free interval,and serum HER2 (extracellular domain) at baseline.

Johnston et al

2 © 2009 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Copyright © 2009 by the American Society of Clinical Oncology. All rights reserved. 2009 from 198.28.69.5.


Availability of archived tumor tissue was required for subsequent biomar-ker analyses. All patients provided signed informed consent, and the pro-tocol was approved by institutional review boards. This study was funded byGlaxoSmithKline (Research Triangle Park, NC) and conducted in accordancewith good clinical practice and all applicable regulatory requirements, includ-ing the 1996 version of the Declaration of Helsinki.

Study Design

This was a randomized, double-blind, controlled, parallel-group, multi-center, phase III study. Patients were stratified by sites of disease (soft tissue/visceral or bone-only disease) and prior adjuvant antiestrogen therapy (� 6months since discontinuation or � 6 months since discontinuation or noprior endocrine therapy). The combination regimen consisted of lapatinib1,500 mg orally and letrozole 2.5 mg orally daily. The control arm consistedof letrozole 2.5 mg daily with matching lapatinib placebo pill. Therapy onboth arms was administered daily until disease progression or withdrawalfrom study. The protocol did not permit crossover of treatment at the timeof progression.

Women were assessed before each 4-week course of therapy, every 12weeks starting at week 108, and at study conclusion or withdrawal. All patientswere observed for survival information. Randomized therapy was perma-nently discontinued for unacceptable toxicity assessed according to the Na-tional Cancer Institute Common Terminology Criteria of Adverse Events(version 3.0) or for the development of grade 3 or 4 interstitial pneumonitis,hepatotoxicity, or cardiac dysfunction. Cardiac evaluations were performed at8-week intervals before week 108 and at 12-week intervals thereafter. Recom-mendations for dose modifications and toxicity management were providedin accordance with US Food and Drug Administration–approved lapatinibprescribing information.29

The primary end point was investigator-assessed PFS, defined as timefrom random assignment until the earliest date of disease progression or deathas a result of any cause in the HER2-positive population. Secondary end pointsincluded overall response rate (ORR); clinical benefit rate (CBR), which wasdefined as complete response, partial response, or stable disease for � 6months; overall survival (OS); safety; and PFS for the intent-to-treat (ITT)HR-positive population. Disease progression and response evaluationswere determined according to Response Evaluation Criteria in Solid Tu-mors (RECIST).30 Measurable disease was not required. The ITT populationincluded all randomly assigned patients regardless of whether they receivedstudy medication. The HER2-positive population included all randomly as-signed patients who had documented HER2 positivity in a commercial labo-ratory31 in primary or metastatic sites defined as either fluorescence in situhybridization positive, 3� staining intensity by immunohistochemistry, or2� by immunohistochemistry and fluorescence in situ hybridization positive.The safety population included all patients who received at least one dose ofrandomized therapy.

Statistical Analysis

Two sample size calculations were performed. A total of 1,280 HR-positive patients were required to ensure that 218 patients with HER2-positivetumors were enrolled to obtain 173 events with 80% power to detect a hazardratio (HR) of 0.645 (� � .05). Additionally, 612 events were needed in the ITTpopulation to provide 90% power to detect an HR of 0.769. To ensure that theoverall type I � error rate was preserved, a closed hierarchical testing procedurewas used, whereby PFS was initially tested in the HER2-positive population atan � level of .05. Testing was performed in the ITT population at an � level of.05 only if statistical significance was achieved in the HER2-positive popula-tion. An Independent Data Monitoring Committee convened on an ongoingbasis to monitor safety data. PFS and OS were summarized using the Kaplan-Meier method and compared between treatment arms using a stratified log-rank test, stratifying for site of disease and prior adjuvant antiestrogen therapy.The date of documented disease progression was defined as the date of eitherradiologic or symptomatic disease progression. To further explore the impactof well-known prespecified baseline prognostic factors (Table 1) on PFS andOS, a predefined stepwise Cox regression model was used.

RESULTS

Patient Population

Between December 9, 2003 and December 29, 2006, 1,286 pa-tients with HR-positive MBC were randomly assigned to receive letro-zole plus lapatinib (n � 642) or letrozole plus placebo (n � 644); ofthese, 17% of patients in each arm had tumors centrally confirmed ina commercial laboratory as HER2 positive (n � 111 and n � 108,respectively). The safety population consisted of 1,278 patients. Figure1 outlines all treatment populations.

Baseline patient and disease characteristics were well balancedbetween treatment arms for both the HER2-positive and ITT HR-positive populations (Table 1). Only three patients received prioradjuvant trastuzumab therapy.

Clinical Efficacy

After a median follow-up time of 1.8 years, median PFS forpatients in the HER2-positive population increased from 3.0 monthsfor letrozole-placebo to 8.2 months for letrozole-lapatinib, demon-strating a significant reduction in the risk of progression for the com-bination (HR � 0.71; 95% CI, 0.53 to 0.96; P � .019; Fig 2A). In theHER2-positive population, the ORR was significantly improved from15% to 28% for patients treated with letrozole-lapatinib (odds ratio[OR] � 0.4; 95% CI, 0.2 to 0.9; P � .021). Including patients withstable disease for � 6 months, the CBR was likewise significantlyimproved (29% to 48%; OR � 0.4; 95% CI, 0.2 to 0.8; P � .003; Fig2B). With less than 50% of OS events yet recorded, the median OS inthe HER2-positive population was 32.3 months in the letrozole-placebo arm compared with 33.3 months in the combination arm(HR � 0.74; 95% CI, 0.5 to 1.1; P � .113; Fig 2C).

The significant result for PFS in the HER2-positive populationallowed for analysis of the ITT HR-positive population by hierarchicaltesting. After a median follow-up of 2 years, median PFS increasedfrom 10.8 months with letrozole-placebo to 11.9 months with thecombination (HR � 0.86; 95% CI, 0.76 to 0.98; P � .026; Fig 3A), andthere was no statistical difference in ORR or CBR between treatmentarms (Fig 3B). In the 952 patients with centrally confirmed HER2-negative tumors, there was no improvement in PFS (HR � 0.90; 95%CI, 0.77 to 1.05; P � .188).

The stepwise Cox regression analysis for PFS adjusting for knownbaseline prognostic factors confirmed the benefit of combinationtherapy in the HER2-positive population (HR � 0.65; 95% CI, 0.47 to0.89; P� .008). After retaining treatment and stratification factors, age(younger), performance status (0), and baseline serum soluble HER2extracellular domain (measured by quantitative enzyme-linked im-munosorbent assay) were identified as being significant. In the HER2-negative population, there was also an impact of combination therapyon PFS, and in addition to the significant baseline factors mentionedearlier, the number of metastatic sites (� three sites) and prior adju-vant antiestrogen stratification were identified as being significant inthe HER2-negative population.

In view of this finding and the relevance of prior tamoxifenexposure in the HER2-negative population on endocrine resistance,an exploratory analysis of predefined prior antiestrogen therapy strat-ification was performed. In the � 6 months since discontinuation/none group (n � 752), 33% of patients had received prior adjuvant

First-Line Lapatinib � Letrozole in Hormone Receptor–Positive MBC

www.jco.org © 2009 by American Society of Clinical Oncology 3



tamoxifen (median duration, 5.0 years); median time since discontin-uation was 3.5 years. The remaining 67% of patients had no priorexposure to hormone therapy. The HR for PFS in this group was 0.94(95% CI, 0.79 to 1.13; P � .522; Fig 4A). The overall CBR was similarbetween the letrozole-lapatinib and letrozole-placebo arms (62% v64%, respectively) within the � 6 months since discontinuation/nonegroup, regardless of PgR status (Fig 4B). In the less than 6 months sincediscontinuation group (n � 200), the median duration of prior adju-vant tamoxifen was 2.8 years; median time since discontinuation wasonly 1 month. By contrast, the HR in this group was 0.78 (95% CI, 0.57to 1.07; P � .117; Fig 5A), with an increase in median PFS from 3.1 to8.3 months favoring the combination. A numerically higher CBR wasfound in the letrozole-lapatinib arm versus letrozole-placebo arm(44% v 32%, respectively; OR � 0.6; 95% CI, 0.3 to 1.1; P � .112; Fig5B), and analysis based on PgR (positive or negative) status showed a

consistent numerical difference in favor of the combination arm,especially for those with PgR-negative tumors, with five (36%) of 14patients having clinical benefit in the letrozole-lapatinib arm versustwo (15%) of 13 patients treated with letrozole alone (Fig 5B). How-ever, by logistic regression analysis, no interaction between treatmentgroup and PgR status was seen.

Safety

Patients received treatment for a median of 40 weeks in theletrozole-lapatinib arm and 38 weeks in the letrozole-placebo arm,with compliance (pill count agreement of � 80%) of more than 95%in both arms. The most common adverse events were diarrhea, rash,nausea, arthralgia, and fatigue (majority were grade 1 or 2), with ahigher incidence in the combination arm for diarrhea and rash (Table2). Of the 60 patients (10%) who had grade 3 or 4 diarrhea in the

0 erroneously received monotherapy

2 erroneously received combination

PFS events in the combination therapy

(n = 88)

PFS events in the monotherapy

(n = 89)


(n = 294)


(n = 342)

Did not receive therapy(n = 0)

Patients with HER2-positive MBC (HER2-Positive Population)†

(n = 219)

Randomly assigned to therapy(n = 219)

Randomly assigned to combination therapy

with lapatinib 1,500 mg + letrozole 2.5 mg po daily

(n = 111)

Randomly assigned to monotherapy with

letrozole 2.5 mg po daily(n = 108)

Randomly assigned to combination therapy with

lapatinib 1,500 mg + letrozole 2.5 mg po daily

(n = 478)



Data lock for protocol-defined analysis as of

03-Jun-08 based on 177 investigator-reported PFS

events||

Investigator-reported PFS events as of 03-Jun-08

(n = 636)

Investigator-reported PFS events in HER2-missing

as of 03-Jun-08(n = 76)

7 erroneously received monotherapy



Patients with HER2-negative MBC (HER2-Negative Population)‡

(n = 952)


2 erroneouslyreceived monotherapy



Patients with HER2-Missing MBC (HER2-Missing Population)§

(n = 115)



(n = 31)


(n = 45)

Randomly assigned to combination therapy

with lapatinib 1,500 mg + letrozole 2.5 mg po daily

(n = 53)



Censored (8 on

combo; n = 23)

Censored (10 on mono; n = 19)

Censored (89 on

combo; n = 184)

Censored (81 on mono;

n = 132)

Censored (6 on

combo; n = 22)

Censored (4 on

mono; n = 17)

PD by radio-logical scans/photos(n = 76)

PD by clinical

PD(n = 9)

Died prior to

PD(n = 3)


PD by clinical

PD(n = 15)

Died prior to

PD(n = 2)


PD by clinical

PD(n = 37)

Died prior to

PD(n = 7)


PD by clinical

PD(n = 37)

Died prior to

PD(n = 14)


PD by clinical

PD(n = 3)

Died prior to

PD(n = 1)


PD by clinical

PD(n = 8)

Died prior to

PD(n = 2)

Patients randomly assigned as of 29-Dec-2006(ITT Population)*

(N = 1,286)

Fig 1. Study design, populations, random assignment, and assessment of events. (*) In the intent-to-treat (ITT) population, 1,088 patients discontinuedtreatment—64% for progression, 5% for consent withdrawal, 10% for an adverse event, 1% for a protocol violation, � 1% for death, � 1% lost to follow-up, and 3%for other reasons (including but not limited to radiation, surgery, scans misread/misinterpreted, and investigator discretion). (†) In the human epidermal growth factorreceptor 2 (HER2) –positive population, 201 patients discontinued treatment—76% for progression, 6% for consent withdrawal, 5% for an adverse event, 1% for aprotocol violation, � 1% for death, and 3% for other reasons. (‡) In the HER2-negative population, 782 patients discontinued treatment—11% as a result of an adverseevent, 4% as a result of consent withdrawn, � 1% as a result of loss to follow-up, 1% as a result of protocol violation, 62% as a result of progression, � 1% as aresult of death, and 3% as a result of other reasons. (§) In the population with HER2 status unknown, 105 patients discontinued treatment—64% for progressivedisease, 10% for consent withdrawal, 10% for an adverse event, � 1% for protocol violation, � 1% lost to follow-up, � 1% for death, and 5% for other reasons. (�)The protocol-defined primary and secondary study analyses were to commence once approximately 173 events (disease progression or deaths on study) had occurredin the HER2-positive population. MBC, metastatic breast cancer; po, orally; combo, combination therapy; mono, monotherapy; PFS, progression-free survival; PD,progressive disease.

Johnston et al




combination arm, 15% required discontinuation. For the remainder,diarrhea was managed by dose reduction (19%), dose interruption(36%), or supportive intervention without treatment dose adjust-ments (31%). Treatment-related LVEF decline and elevation of liverfunction transaminases were infrequent. Seven patients had a symp-tomatic LVEF decline—two patients (0.3%) on letrozole-placebo andfive patients (0.8%) on lapatinib-letrozole). One patient on theletrozole-placebo arm was thought to have had drug-induced liverinjury (ALT/AST � 3� upper limit of normal, total bilirubin � 1.5�upper limit of normal, and alkaline phosphatase � 2� upper limit of

normal) compared with eight patients on the combination arm. Twoof the eight women on the combination arm and the patient in theletrozole-placebo arm required drug discontinuation, with resolutionof liver function tests thereafter; the other six patients resolved labora-tory abnormalities without drug discontinuation. Any serious adverseevent related to study drug occurred in 8% of patients receiving thecombination compared with 4% of patients receiving letrozole-placebo. There were a total of 16 fatalities related to serious adverseevents (eight deaths in each arm), of which only three were deemedrelated to study drug (one in letrozole-lapatinib arm [hepatobiliary]and two in letrozole-placebo arm [one cardiac, one dyspnea]). No newor unexpected safety signals for either drug were identified.

DISCUSSION

Coexpression of HER2 in HR-positive breast cancer confers rela-tive endocrine resistance, and preclinical models have used tar-geted strategies to enhance efficacy of either tamoxifen or estrogendeprivation.13,14,32-34 The Trastuzumab in Dual HER2 ER-PositiveMetastatic Breast Cancer (TAnDEM) trial evaluated anastrozolewith or without the addition of trastuzumab in HR-positive, HER2-positive MBC (n � 208)9 and showed that the combined approachhad a significant benefit for PFS. Our study demonstrated that in asimilar HR-positive, HER2-positive population (n � 219), the com-bination of letrozole and lapatinib significantly prolonged PFS

A

0

Letrozole + lapatinib

Patients at risk

P = .019

Letrozole 2.5 mg + lapatinib 1,500 mg(88 events; median PFS, 8.2 mo)Letrozole 2.5 mg + placebo(89 events; median PFS, 3.0 mo)

Letrozole

Aliv

e W

ithou

tPr

ogre

ssio

n (%

)

Time Since Random Assignment (months)

100

80

60

40

20

105 2015 3025 4035 5045

B

Patie

nts

(%)

70

60

40

50

30

20

10

C

0


Patients at risk

Letrozole 2.5 mg + lapatinib 1,500 mgLetrozole 2.5 mg + placebo

Letrozole

Surv

ivin

g (%

)


100

80

60

40

20

105 2015 3025 4035 5045

111 69 33 20 12 8 4 1 1

108 43 26 18 12 7 5 2 2

111 104 89 80 64 48 32 19 9 4

108 93 76 69 59 38 31 15 8 2

Letrozole 2.5 mg + placeboLetrozole 2.5 mg + lapatinib 1,500 mg

P = .021

15%

4%

28%

5%11%

23%

14%20%

29%

48%P = .003

CR PR SD ≥ 6 mo ORR CBR

Fig 2. Clinical efficacy in human epidermal growth factor receptor 2–positivepopulation. (A) Kaplan-Meier estimates of progression-free survival (PFS), (B)response rates and clinical benefit rates (CBR), and (C) Kaplan-Meier estimates ofoverall survival. CR, complete response; PR, partial response; SD, stable disease;ORR, overall response rate.

A

0


Patients at risk

P = .026

Letrozole 2.5 mg + lapatinib 1,500 mg(413 events; median PFS, 11.9 mo)Letrozole 2.5 mg + placebo(476 events; median PFS, 10.8 mo)

Letrozole

Aliv

e W

ithou

tPr

ogre

ssio

n (%

)


100

80

60

40

20

105 2015 3025 4035 5045

Patie

nts

(%)

70

60

40

50

30

20

10

B Letrozole 2.5 mg + placeboLetrozole 2.5 mg + lapatinib 1,500 mg

CR PR SD ≥ 6 mo ORR CBR

32% 33%

4% 5%

27% 28% 25% 26%

56% 58%

642 438 294 208 120 78 51 26 11 2

644 403 291 212 140 80 53 23 13 7

P = .761

P = .726

Fig 3. Clinical efficacy in intent-to-treat population. Kaplan-Meier estimates of(A) progression-free survival (PFS) and (B) response rates and clinical benefitrates (CBR). CR, complete response; PR, partial response; SD, stable disease;ORR, overall response rate.





compared with letrozole alone (median PFS, 8.2 v 3.0 months respec-tively), representing a statistically significant 29% reduction in the riskof disease progression. Consistent with these findings, a superior CBR(48% with letrozole-lapatinib v 29% with letrozole alone) and trendtoward improvement in OS were also seen. This trial demonstratedthat for HR-positive, HER2-positive patients with MBC, the com-bination of letrozole and lapatinib is superior to an AI plus placebo.

Importantly, the population of women with HER2-positiveMBC treated in the studies discussed earlier differ significantly frompatients enrolled onto two randomized trials of first-line taxane-basedchemotherapy with or without trastuzumab that showed a survivaladvantage with the addition of targeted therapy.35,36 In the endocrinestudies, all patients with HER2-positive MBC had HR-positive diseasecompared with only 40% to 60% of patients in the chemotherapystudies; also, patients in the endocrine studies were older (median age,60 v 53 to 55 years, respectively) and had a lower incidence of visceralmetastases. Although each of the four trials confirmed a benefit withthe addition of a targeted therapy over endocrine or chemotherapyalone, these differences in populations preclude direct comparisons.Our study supports letrozole-lapatinib as a possible therapeutic ap-proach to control HR-positive, HER2-positive MBC in appropriate

patients for a significant period of time before chemotherapy andtrastuzumab are required.

In HR-positive breast carcinomas that are initially HER2 nega-tive, EGFR and HER2 pathways may become upregulated on devel-opment of endocrine resistance, and a combined growth factorreceptor– and endocrine-targeted approach could delay acquired re-sistance.37,38 Clinically, for patients who relapse during adjuvant ther-apy with tamoxifen-resistant MBC where growth factor receptors mayhave become upregulated, dual targeted therapy could enhance theobjective response rate compared with AIs alone. Alternatively, inhormone-sensitive MBC without prior tamoxifen exposure, com-bined therapy could delay the emergence of acquired resistance overtime by preventing upregulation of growth factor receptors. Osborneet al15 demonstrated a trend toward improved PFS for the addition ofthe EGFR TKI gefitinib to tamoxifen versus tamoxifen alone in pa-tients who were either endocrine naïve or more than 12 months sincecompletion of prior adjuvant endocrine therapy (median PFS, 10.9 v8.8 months, respectively; HR � 0.84; 95% CI, 0.59 to 1.18; P � .31); ina small subset of patients with known HER2-positive tumors (n �37),an improvement in PFS was also seen (median PFS, 6.7 v 5.8 months,respectively; HR � 0.54; 95% CI, 0.25 to 1.15; P � .11). In 93 HR-positive MBC patients, Cristofanilli et al16 reported prolongation of

A

0


Patients at risk

P = .522

Letrozole 2.5 mg + lapatinib 1,500 mg(median PFS, 14.7 mo)Letrozole 2.5 mg + placebo(median PFS, 15.0 mo)

Letrozole

Aliv

e W

ithou

tPr

ogre

ssio

n (%

)


100

80

60

40

20

105 2015 3025 4035 5045

Patie

nts

(%)

70

80

60

40

50

30

20

10

B Letrozole 2.5 mg + placeboLetrozole 2.5 mg + lapatinib 1,500 mg

Overall CBR PgR+ PgR-

382 282 202 147 87 55 37 20 7 1

370 283 214 158 106 62 41 16 9 6

62%

236382

64%

235370

63%68%

59%58%

169269

178263

3458

3153

Fig 4. Clinical efficacy in the human epidermal growth factor receptor2–negative population predefined subgroup with an interval of � 6 monthssince discontinuation of prior adjuvant tamoxifen or no prior adjuvant tamoxifen.(A) Kaplan-Meier estimates of progression-free survival (PFS) and (B) responseand clinical benefit rates (CBR). Progesterone receptor (PgR) status was mea-sured only in known estrogen receptor–positive patients.

A

0


Patients at risk

P = .117

Letrozole 2.5 mg + lapatinib 1,500 mg(median PFS, 8.3 mo)Letrozole 2.5 mg + placebo(median PFS, 3.1 mo)

Letrozole

Aliv

e W

ithou

tPr

ogre

ssio

n (%

)


100

80

60

40

20

105 2015 3025 4035 5045

Patie

nts

(%)

70

80

60

40

50

30

20

10

BLetrozole 2.5 mg + placeboLetrozole 2.5 mg + lapatinib 1,500 mg

Overall CBR PgR+ PgR-

96 53 36 25 15 10 8 3

104 43 31 21 14 9 5 4 1

44%

32%

47%

37% 36%

15%

4296

33104

3472

2978

514

213

Fig 5. Clinical efficacy in the human epidermal growth factor receptor2–negative population predefined subgroup with an interval of less than 6months since discontinuation of prior adjuvant tamoxifen. (A) Kaplan-Meierestimates of progression-free survival (PFS) and (B) response and clinical benefitrates (CBR). Progesterone receptor (PgR) status was measured only in knownestrogen receptor–positive patients.

Johnston et al




PFS with the addition of gefitinib to anastrozole compared with anas-trozole alone (median PFS, 14.6 v 8.2 months, respectively; HR�0.55;95% CI, 0.32 to 0.94). In both trials, no information was provided onthe number of patients who were totally endocrine naïve or hadreceived prior tamoxifen, which could be an important predictorfor benefit from combined therapy in delaying time to progressionof disease.

In this study, 952 patients with HR-positive MBC were con-firmed centrally as having original HER2-negative primary breastcancer. In addition, the protocol predefined a stratification based onprior adjuvant antiestrogen exposure. In the 752 patients with � 6months since discontinuation of antiestrogen therapy or no priorantiestrogen therapy, two thirds had no prior endocrine therapy, andone third had taken tamoxifen for a median of 5 years, with at least 3years since discontinuation. Essentially, this represents a hormone-sensitive population. The efficacy data show that in the endocrine-sensitive population, there was no significant improvement in PFS orCBR for the combination (Fig 4). In contrast, the 200 patients whoexperienced relapse less than 6 months since discontinuation had allreceived tamoxifen for a median of 2.9 years and entered the studywith a median of less than 1 month since discontinuation. Thesepatients would be considered clinically relatively tamoxifen resistant,and in this group, a statistically nonsignificant trend toward improve-ment in both PFS and CBR was seen (Fig 5). These data in theHER2-negative population suggest that there is no benefit for theaddition of an EGFR/HER2-targeted therapy to an AI in an HR-positive, HER2-negative, endocrine-sensitive or -naïve MBC popula-tion but suggest there could be possible benefit for patients whoexperience relapse early during adjuvant tamoxifen therapy (consis-tent with preclinical models where growth factor activity is enhancedin association with endocrine resistance).10,34,37,38 Lack of PgR expres-

sion has been suggested as a surrogate for enhanced growth factorreceptor activity in ER-positive breast cancer,39,40 and although atrend in favor of clinical benefit from the combination was observed intamoxifen-resistant patients with PgR-negative tumors, the numbersin this subset are too small to draw definitive conclusions, and overall,no substantial benefit in favor of PgR-negative tumors was seen inthis trial. Primary tumors have been collected from more than 80%of patients enrolled onto the trial; further biomarker studies intamoxifen-treated patients are clearly warranted to identify a tumorphenotype that may predict relapse and subsequent benefit fromcombined letrozole and lapatinib.

The inability of lapatinib to delay progression with letrozole inthe endocrine-sensitive, HR-positive, HER2-negative population is incontrast to the preclinical37,38 and clinical15,16 data reported with theEGFR TKI gefitinib. One potential explanation is that tamoxifenmay induce different endocrine resistance pathways to aromataseinhibition. Specifically, tamoxifen has been demonstrated in pre-clinical models to enhance upregulation of EGFR and HER2.11,38

Consequently, gefitinib may synergize well with tamoxifen inendocrine-sensitive disease to delay EGFR/HER2 activation. In con-trast, aromatase inhibition may induce different resistance pathwaysto tamoxifen and, when combined with an EGFR/HER2 inhibitor inendocrine-sensitive disease, may fail to provide added benefit. Theinitial benefit seen with gefitinib plus anastrozole in a small phase IIstudy16 was not observed in a second randomized phase II trial withthe combination.41 Our study showed that lapatinib plus letrozolefailed to delay endocrine resistance in more than 750 patients withendocrine-sensitive, EGFR/HER2-negative disease. Indeed, this lackof benefit in hormone-sensitive breast cancer was demonstrated pre-clinically by the failure of trastuzumab and letrozole when combined

Table 2. Adverse Events

Adverse Event

Letrozole � Placebo (n � 624) Letrozole � Lapatinib (n � 654)

Grade 1 Grade 2 Grade 3 Grade 4 Grade 1 Grade 2 Grade 3 Grade 4

No. % No. % No. % No. % No. % No. % No. % No. %

Diarrhea� 91 15 27 4 6 � 1 0 0 210 32 147 22 58 9 2 � 1Rash� 68 11 15 2 0 0 0 0 186 28 100 15 7 1 0 0Nausea� 85 14 40 6 4 � 1 0 0 141 22 53 8 6 � 1 0 0Arthralgia 100 16 37 6 8 1 0 0 81 12 39 6 7 1 0 0Fatigue 63 10 42 7 3 � 1 0 0 77 12 47 7 10 2 0 0Back pain 41 7 42 7 13 2 1 � 1 50 8 42 6 12 2 0 0Vomiting� 42 7 21 3 4 � 1 1 � 1 63 10 38 6 7 1 1 � 1Headache 52 8 28 4 3 � 1 0 0 63 10 26 4 2 � 1 0 0Cough 73 12 15 2 2 � 1 0 0 59 9 19 3 2 � 1 0 0Hot flush� 65 10 27 4 0 0 0 0 54 8 12 2 3 � 1 0 0Asthenia 45 7 19 3 5 � 1 0 0 55 8 20 3 5 � 1 0 0Pain in extremity 42 7 24 4 5 � 1 0 0 39 6 25 4 2 � 1 0 0Dyspnea 36 6 27 4 7 1 2 � 1 31 5 27 4 5 � 1 1 � 1Pruritus� 43 7 11 2 1 � 1 0 0 54 8 23 4 2 � 1 0 0Alopecia� 44 7 1 � 1 0 0 0 0 82 13 2 � 1 1 � 1 0 0Constipation 48 8 17 3 2 � 1 0 0 54 8 6 � 1 0 0 0 0Anorexia 34 5 18 3 2 � 1 0 0 51 8 16 2 5 � 1 0 0Dry skin 25 4 2 � 1 0 0 0 0 71 11 15 2 1 � 1 0 0Epistaxis 7 1 3 � 1 1 � 1 0 0 63 10 6 � 1 1 � 1 0 0Nail disorder 5 � 1 1 � 1 0 0 0 0 60 9 11 2 1 � 1 0 0

�A statistically significant (P � .05) effect was observed between treatment groups for the total incidence of these adverse events.





from the outset to delay endocrine resistance in HR-positive xeno-grafts, albeit that combined therapy was effective at the time resistanceto letrozole had developed.42

In summary, this trial confirmed that for patients with knownHR-positive, HER2-positive MBC, a combined targeted therapy ap-proach is superior to endocrine therapy alone. The letrozole-lapatinibcombination was well tolerated and produced a clinically meaningfulimprovement in several efficacy end points. As such, combinationtherapy with lapatinib and letrozole could be considered an effec-tive treatment option for patients with known HR-positive, HER2-positive MBC.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Although all authors completed the disclosure declaration, the followingauthor(s) indicated a financial or other interest that is relevant to the subjectmatter under consideration in this article. Certain relationships markedwith a “U” are those for which no compensation was received; thoserelationships marked with a “C” were compensated. For a detaileddescription of the disclosure categories, or for more information aboutASCO’s conflict of interest policy, please refer to the Author DisclosureDeclaration and the Disclosures of Potential Conflicts of Interest section inInformation for Contributors.Employment or Leadership Position: Julie Maltzman, GlaxoSmithKline(C); Allison Florance, GlaxoSmithKline (C); Lisa O’Rourke,GlaxoSmithKline (C); Cristina Oliva, GlaxoSmithKline (C); Steven Stein,GlaxoSmithKline (C) Consultant or Advisory Role: Xavier Pivot, Roche(C), GlaxoSmithKline (C), Novartis (C); Veronique Dieras,GlaxoSmithKline Breast Advisory Board (C), Novartis Advisory Board(C); Alexey Manikhas, GlaxoSmithKline (C); M. John Kennedy,GlaxoSmithKline (C); Michael F. Press, GlaxoSmithKline (C),Genentech (C); Mark Pegram, GlaxoSmithKline (C) Stock Ownership:

Julie Maltzman, GlaxoSmithKline; Allison Florance, GlaxoSmithKline;Lisa O’Rourke, GlaxoSmithKline; Steven Stein, GlaxoSmithKlineHonoraria: Stephen Johnston, GlaxoSmithKline; John Pippen Jr,AstraZeneca, Genentech, GlaxoSmithKline; Xavier Pivot, Roche,Cephalon; Saeed Sadeghi, GlaxoSmithKline; Veronique Dieras,Lecture Symposium; Henry Leonidas Gomez, GlaxoSmithKline,Bristol-Myers Squibb, AstraZeneca; Michael F. Press,GlaxoSmithKline, Genentech; Mark Pegram, GlaxoSmithKlineResearch Funding: Stephen Johnston, GlaxoSmithKline; XavierPivot, Roche, Amgen; Alexey Manikhas, GlaxoSmithKline; M. JohnKennedy, GlaxoSmithKline; Michael F. Press, GlaxoSmithKline,Genentech Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Stephen Johnston, Julie Maltzman, LisaO’Rourke, Cristina Oliva, Steven Stein, Mark PegramAdministrative support: Julie Maltzman, Lisa O’RourkeProvision of study materials or patients: Stephen Johnston, JohnPippen Jr, Xavier Pivot, Mikhail Lichinitser, Saeed Sadeghi, VeroniqueDieras, Henry Leonidas Gomez, Gilles Romieu, Alexey Manikhas, M.John Kennedy, Julie Maltzman, Lisa O’Rourke, Mark PegramCollection and assembly of data: Saeed Sadeghi, Michael F. Press, JulieMaltzman, Allison Florance, Lisa O’Rourke, Steven SteinData analysis and interpretation: Stephen Johnston, Xavier Pivot,Veronique Dieras, Michael F. Press, Julie Maltzman, Allison Florance,Lisa O’Rourke, Cristina Oliva, Steven Stein, Mark PegramManuscript writing: Stephen Johnston, Xavier Pivot, Michael F. Press,Julie Maltzman, Allison Florance, Lisa O’Rourke, Cristina Oliva, StevenStein, Mark PegramFinal approval of manuscript: Stephen Johnston, John Pippen Jr, XavierPivot, Saeed Sadeghi, Veronique Dieras, Gilles Romieu, M. JohnKennedy, Michael F. Press, Julie Maltzman, Lisa O’Rourke, CristinaOliva, Steven Stein, Mark Pegram

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■ ■ ■

Acknowledgment

We would like to acknowledge the women who participated in this study as well as the investigators and their staff; the members of theIndependent Data Monitoring Committee; Tim Kelly from GlaxoSmithKline; Novartis Oncology; and The Phillips Group for technical

assistance in preparation of the article.

Appendix

The following investigators and institutions also participated in the study: S. Abadie-Lacourtoisie, Center Paul Papin, Angers, France; W.Abenhardt, Gemeinschaftspraxis Hematologie and Internistische Onkologie, Munchen, Germany; E. Alba, Hospital C.U. Virgen de laVictoria, Malaga, Spain; J. Ales, Hospital Ruber Internacional Medical Oncology Department C/La Maso, Madrid, Spain; H.J. Allen,Comprehensive Cancer Centers of Nevada, Las Vegas, NV; I. Alvarez Lopez, Hospital de Donostia, San Sebastian, Spain; D.M. Anderson,St. Francis Regional Medical Center, Shakopee, MN; M. Andersson, Rigshospitalet Onkologisk, Koebenhavn Oe, Copenhagen, Denmark;A. Anton, Hospital Miguel Servet Paseo Isabel La Catolica, Zaragoza, Spain; A. Ardizzoni, Unita Operativa di Oncologia Medica, Parma,Italy; R. Asbury, Interlakes Oncology & Hematology, Rochester, NY; L. Assersohn, St Georges Hospital, London, United Kingdom; Z.Aziz, Jinnah Hospital, Faisal Town, Lahore, Pakistan; G. Baake, Fahltakamp, Pinneberg, Germany; M. Baki, Fovarosi OnkormanyzatSzent Margit Korhaz, Budapest, Hungary; G. Beadle, Royal Brisbane & Women’s Hospital, Brisbane, Australia; J.V. Beattie, MissouriCancer Care, St. Charles, MO; S. Ben Ahmed, Hopital Ferhat Hached, Taoufik, Tunisia; J. Bines, Instituto Nacional do Cancer, Rio deJanciro, Brazil; R. Blachly, Northeast Arkansas Clinic, Jonesboro, AR; M. Blees, Leuzenbacher, Altenkirchen, Germany; J. Blondal, St.Joseph’s Health Centre, Ontario, Canada; E. Bobbio Pallavicini, Ospedale Maggiore Di Crema, Crema, Italy; V. Borisov, City OncologyClinical Center, Moscow, Russia; L.D. Bosserman, The Robert & Beverly Lewis Family Cancer Care Center, Pomona, CA; H. Boussen,Institute Saleh Azaiez, Tunis, Tunisia; H. Boussen, Polyclinique Taoufik, Tunis, Tunisia; M. Bozac, Djelatnost za Interne Bolesti, OpcaBolnica Pula, Croatia; T.W. Brotherton, Danville Hematology & Oncology, Inc, J, Danville, VA; O. Brudler, Hamatologisch-Onkologische Praxis Augsburg, Augsburg, Germany; G. Calderillo-Ruiz, Hospital Medica Sur, Mexico; O. Camara, Universitaetsklini-kum Jena Klinik fur Fraueheikunde and Geburtshilfe, Jena, Germany; B. Cantos, Clinica Puerta de Hierro, C/San Martin de Porres 4Farmacologia Clinica, Madrid, Spain; J. Cardenas-Sanchez, Centro Estatal de Cancerologia de Colima, Colima, Mexico; C. Carmen,Hospital Ramon y Cajal, Madrid, Spain; R.R. Carroll, Robert R. Carroll MD PA, Gainesville, FL; J. Castellanos, Hospital General IsIas Cics,Vigo, Spain; D. Chan, Cancer Care Associate Medical Group, Inc, Redondo Beach, CA; J. Chang, DRCC Lakeridge Health, OshawaCanada; H.C. Chung, Yonsei University College of Medicine, Seoul, Korea; E. Ciruelos, Hospital Doce de Octubre, Madrid, Spain; V.





Cohen, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Canada; S. Cold, Odense University Hospital, Odense, Denmark; R.E.Coleman, Sheffield Teaching Hospital National Health Service (NHS) Trust, Sheffield, United Kingdom; F.A. Collichio, University ofNorth Carolina Hospital, Chapel Hill, NC; H.J. Cordes, Stresemannallee 3, Frankfurt, Germany; G.J. Creemers, Catharina Ziekenhuis, theNetherlands; J. Crown, St. Vincent’s Hospital, Dublin, Ireland; N. Davidson, Broomfield Hospital, Chelmsford, Essex, United Kingdom;S.J. Davidson, The Thomas and Dorothy Leavey Cancer Center, Northridge, CA; A. Davis, The Canberra Hospital, Garran-AustralianCapital Territory, Canberra, Australia; P.C. De Jong, St. Antonius Ziekenhuis, Nieuwegein, the Netherlands; J. De La Cruz-Vargas, TorreMedica Cristobal Colon Segunda, Guerrero, Mexico; A. Decensi, S.C. Oncologia Medica e Preventiva, Genova, Italy; S. Delaloge, InstitutGustave Roussy, Villejuif, France; S. Diab, Rocky Mountain Cancer Center, Denver, CO; R.A. Dichmann, Central Coast MedicalOncology Corporation, Santa Maria, CA; V. Dieras, Institut Curie, Paris, France; L. Dreosti, Pretoria Academic Hospital, Pretoria, SouthAfrica; J. Dufresne, Centre Hospitalier Universitaire de Sherbrooke Hopital, Fleurimont, Canada; W. Eiermann, Fraunklinik vom RotenKreuz, Munchen, Germany; A. Elias, University of Colorado Health Science Center, Aurora, CO; F.L.G. Erdkamp, Maasland ZiekenhuisSittard, Sittard, the Netherlands; L. Fehrenbacher, Kaiser Permanente Medical Center, Vallejo, CA; E. Filipczyk-Cisarz, DolnoslakieCentrum Onkologii, Wroclow, Poland; R.E. Fisher, Longmont Clinic, Longmont, CO; P. Flynn, Metro-Minnesota Community ClinicalOncology Program (CCOP), St Louis Park, MN; A. Former Pi-Majlis, Providencia, Santiago, Chile; H. Forstbauer, Schlossstr. 18,Troisdorf, Germany; S.X. Francko, Memorial Cancer Institute/Breast Cancer Center, Hollywood, FL; M. Frikha, Hopital Habib Bour-guiba, Sfax, Tunisia; S. Fuxius, Kurfuerstenanlage 34, Heidelberg, Germany; J. Gapski, Trillium Health Centre, Ontario, Canada; C.E.Geyer, Allegheny General Hospital, Pittsburgh, PA; D.D. Gibbs, Christchurch Hospital, Christchurch, New Zealand; G. Gill, RoyalAdelaide Hospital, Adelaide, Australia; M. Glados, Suedring 15, Coesfeld, Germany; S. Gluck, University of Miami Hospital and Clinics,Miami, FL; L. Goldstein, Fox Chase Cancer Center, Philadelphia, PA; H.M. Gomez, Instituto Nacional de Enfermedades Neoplasicas,Lima, Peru; V. Gorbunova, Russian Oncological Research Center after N.N. Biokhin RAMS, Russia, Moscow; G. Grana, The CancerInstitute of New Jersey at Cooper, Voorhees, NJ; D. Grenier, Cancer Care Manitoba, Manitoba, Canada; L. Grogan, Beaumont Hospital,Dublin, Ireland; R. Gupta, Mid West Regional Hospital, Limerick, Ireland; M. Gupta, Dokota Clinic LTD, Fargo, ND; J. Gurtler, Metairie,LA; M.K. Hagan, Virginia Cancer Institute, Richmond, VA; H.A. Hahm, Northwest Georgia Oncology Centers, P.C., Marietta, GA; B.Haley, University of Texas Southwestern Medical Center, Dallas, TX; M. Hansen, Hilleroed Sygehus Medicinsk Dagafsnit, Denmark;W.G. Harker, Utah Cancer Specialists, Salt Lake City, UT; E. Hoering, Gemeinschaftspraxis Gastroenterologie/Hematology, Stuttgart,Germany; G. Hu, Kelsey–Seyboid Clinic, Houston, TX; E.H. Hu, Central Hematology Oncology Medical Group, Inc, Alhambra, CA;P.S.G.J. Hupperets, AZM, Maastricht, the Netherlands; S. Hurvitz, University of California, Los Angeles, Los Angeles, CA; N. Iannotti,Hematology/Oncology Associates of the Treasure Coast, Port St Lucie, FL; Y.H. Im, Samsung Medical Centre, Seoul, Korea; F.J.F.Jeurissen, MC Haaglanden, Den Haag, the Netherlands; J.K. Joffe, Calderdale and Huddersfield NHS Trust, Huddersfield, UnitedKingdom; S.RD. Johnston, Royal Marsden Hospital, London, United Kingdom; A Jones, Royal Free Hospital, London, United Kingdom;K.M. Josten, Aukammallee 33, Wiesbaden, Germany; K. Kammerer, Pest Megyei Flor Ferenc Korhaz Onkologia Osztaly, Semmelweis,Hungary; F.C. Kass, Santa Barbara Hematology Oncology Medical Group, Inc, Santa Barbara, CA; M. Keane, University College Hospital,Galway, Ireland; J. Kennedy, St. Jame’s Hospital, Dublin, Ireland; P. Kennedy, Metropolitan Hematology/Oncology Medical Group, LosAngeles, CA; A. Kleine-Tebbe, Charite-Campus Virchow Klinikum-Gynaekologie, Berlin, Germany; H. Kluger, Yale University School ofMedicine, New Haven, CT; A. Korfel, Medizinische Klinik III, Berlin, Germany; R. Kreienberg, Universitatesklinikum Ulm, Ulm,Germany; E.D. Kreuser, Krankenhaus der Barmherzige Brueder, Ragensburg, Germany; S. Kurbel, Klinika za Onkologiju, KB Osijek,Croatia; R.M. Langdon, Nebraska Methodist Hospital, Omaha, NE; G.L. Lerzo, Hospital de Oncologia Maria Cure, Buenos Aires,Argentina; M. Lichinitser, Russian Oncological Research Center after N.N. Biokhin RAMS, Moscow, Russia; A.K.D. 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Johnston et al




California, San Diego Medical Center, San Diego, CA; R. Patel, Comprehensive Blood and Cancer Center, Bakersfield, CA; M.D. Pegram,Sylvester Comprehensive Cancer Center, Miami, FL; C.A.S. Pereira Filho, Clínica de Assistencia Multidisciplinar em Oncologia, Bahía,Brazil; G. Perez-Manga, Hospital Gregorio Maranon, Madrid, Spain; T. Pienkowski, Maria Sklodowska-Curie Memorial Cancer Centre,Warsaw, Poland; P. Pimentel, Hospital Alberto Sabogal Jiron Colina, Lima, Peru; J.E. Pippen, P.A. Sammons Cancer Center, Dallas, TX;X. Pivot, Hopital Jean Minjur, Besancon, France; J. Polikoff, Southern California Permanente Medical Group, San Diego, CA; L.Provencher, Centre Hospitalier Affilie Universitaire de Quebec, Quebec, Canada; B.T. Pruitt, Don & Sybil Harrington Cancer Center,Amarillo, TX; J. Raats, Panorama Medi-clinic, Panorama Cape Town, South Africa; S.M. Raza, Shaukat Khanum Memorial CancerHospital & Research Centre, Mohammad Ali Johar Town, Lahore, Pakistan; D.W. Rea, Sandwell and West Birmingham Hospitals NHSTrust, W. Midland, United Kingdom; J. Reyes-Vidal, Clinica Las Condes, Santiago, Chile; J. Rifa, Hospital Son Dureta, Mallorca, Spain;J. Rimailho, Centre Hospitalier Universitaire (CHU) Paul de Viguier, Toulouse, France; K. Rinn, Swedish Cancer Institute, Seattle, WA;J.S. Ro, National Cancer Center, Gyeonggi-do, Korea; C.J. Rodenburg, Meander MC, loc. St Elisabeth, Amersfoort, the Netherlands; J.Rolski, Chemotherapy Department Oncology Centre, Krakow, Poland; G. Romieu, Centre Val d’Aurelle-Paul Lamarque, Montpellier,France; M. Roselli, Oncologia Medica, Dipartimento di Medicina Interna, Rome, Italy; J.-A. Roy, Hospital du Sacre Coeur de Montreal,Montreal, Quebec, Canada; J. Rubins, Interlakes Oncology & Hematology, Rochester, NY; S. Sabesan, The Townsville Hospital,Queensland, Australia; R.A. Saez, Watson Clinic LLP, Lakeland, FL; M.N. Saleh, Georgia Cancer Specialists, Tucker, GA; P. Salman,Fundacion Arturo Lopez Perez, Santiago, Chile; J. Sanchez, Hospital Universitario San Ignacio, Bogota, Colombia; V. Schulz, SystemedicGmbH, Kiel, Germany; L.S. Schwartzberg, The West Clinic, Memphis, TN; C.W. Seidler, Fallon Clinic, Inc at Worcester Medical Center,Worcester, MA; V. Semiglazov, Petrov Research Institute of Oncology, St. Petersburg, Russia; F. Senecal, Northwest Medical Specialties,Tacoma, WA; T. Siddiqui, Shands Teaching Hospital, Gainesville, FL; S. Siena, Ospedale Niguarda CA�Granda, Milan, Italy; J.D. Skelton,Boca Raton Community Hospital Inc, Boca Raton, FL; B.G. Sleckman, St John’s Mercy Medical Center, St Louis, MO; H.P. Sleeboom,Ziekenhuis Leyenburg, Den Haag, the Netherlands; P.G. Soerensen, Amtssygehuset I Roskilde, Roskilde, Denmark; L. Sreter, SemmelweisEgyetem, Altalanos Orvostudomanyi Kar, Budapest, Hungary; V. Stahalova, FNB – Ustav Radiacni Onkologie, Praha, Czech Republic;A.M. Storniolo, Indiana University Hospital, Indianapolis, IN; I. Szanto, Fovarosi Onkormanyzat Szent Istvan Korhaz, Budapest,Hungary; M. Szucs, Bacs-Kiskun Megye Onkormanyzati Korhaza, Nyiriu, Hungary; J.A. Taguchi, Sansum Santa Barbara MedicalFoundation Clinic, Santa Barbara, CA; H.W. Tessen, Koesler Str. 10b, Goslar, Germany; A. Thomas, Universitaetsklinikum Charite Klinikfur Frauenheilkunde und Geburtehilfe, Berlin, Germany; S.P. Thomas, Oncology Hematology Associates of Central Illinois, Peoria, IL; L.Thurzo, Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Orvos’es, Koranyi Fasor, Hungary; C. Timcheva, National Center of Oncology,Sofia, Bulgaria; A. Tomova, Department of Chemotherapy, Oncological Dispensary, Plovdiv, Bulgaria; V. Trillet-Lenoir, CH Lyon SudService Oncologie Medicale, Pierre Benite, France; J. Tujakowski, Regional Oncology Centre, Bydgoszcz, Poland; V. Tzekova, MedicalUniversity, Sofla Bulgaria; M. Unsal, SSK Okmeydam Hospital, Istanbul, Turkey; L. Vanlemmens, Centre Oscar Lambret, Lille, France;C.A. Vargas, Fundacion Santa Fe De Bogota, Bogota, Colombia; J. Vidal, Hospital Josep Trueta Servicio de Oncologie Avda de Franca,Girona, Spain; E.E. Voest, University Medical Center Utrecht, Utrecht, the Netherlands; C.L. Vogel, Comprehensive Cancer CareSpecialists at Boca Raton Lynn Regional Cancer Center-West, Boca Raton, FL; F. Von Koch, Klinikum der Universitat Munchen,Munchen, Germany; K. Von Maillot, Frauenklinik des Ostalbklinikums Aalen Brust Centrum, Germany; G. Von Minckwitz, Klinikumder Johann Wolfgand, Goethe-Universist Geburtshilfe, Frankfurt, Germany; E. Vrdoljak, Klinika za Onkologiju, Split, Croatia; A.M.Wardley, Christie Hospital NHS Trust, Manchester, United Kingdom; M. Wood, Fletcher Allen Health Care, Burlington, VT; P.Wuelfing, Universitatsklinikum Munster Klinik und Poliklinik fur Frauenheilkunde und Geburtshilfe, Munster, Germany; L. Yelle,Hopital Notre-Dame, Universite de Montreal, Montreal, Quebec, Canada; J. Younus, London Health Sciences Centre, London, UnitedKingdom; J. Zaluski, Wielkopolskie Centrum Onkologii, Poznan, Poland.





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