Cáncer de mama avanzado: Algoritmos terapéu8cos · Cáncer de Mama Agresivo Her2- en Primera...

Cáncerdemamaavanzado:Algoritmosterapéu8cos

MªIsabelGallegosSanchoComplejoAsistenciadeSegoviaSegovia7deMayodel2016

Ø Manejoterapéu-cosegúnsub-posintrínsecos

Luminales:Ttoshormonalesynuevosagentes

HER-2:TerapiaBiológica

TripleNega8vas:Nuevosagentes,situaciónactual

GUIAS ASCO Y NCCN

Progresos en el Tratamiento del Cáncer de Mama

§  No es una sola enfermedad

§  Grupo de subtipos tumorales (Her2-positivo; RH+; RH-; Her2-negativo):

ü  con diferente historia natural

ü  y que requieren diferentes aproximaciones terapéuticas

Mejorcomprensióndelabiologíadelcáncerdemama

Racionaldesarrollodetratamientoscontradianasmoleculares

Mejoríadelpronós-coytratamiento

Correlación entre clasificación molecular y fenotipo por inmunohistoquímica Correlación entre clasificación molecular y fenotipo por

inmunohistoquímica

CLASIFICACIÓNFENOTÍPICADELCÁNCERDEMAMA

LUMINALES

AF-1

AF-2

DNA binding

ENFERMEDAD LUMINAL, RH + HER2 -

Ø  La terapia endocrina debe ser la primera opción, sólo QT ante situaciones de enfermedad rápidamente agresiva ( crisis visceral) o clara situación de

Resistencia Endocrina ( I, A)

‘Survivorship’ in ABCThe complex needs of patients living with ABC, at times formany years, as well as their caregivers, should be addressed notonly in terms of supportive and palliative care but also regarding‘survivorship’ concerns. The multidisciplinary approach of ABCshould encompass early in the history of the disease not onlyphysical, but also functional, social, psychological, and spiritual,domains [25–27].It is important to clearly define the disease context with

patients and families, addressing the concept of uncertainty andtailoring the treatment strategy according to individual prioritiesand disease status [28]. Specific psychosocial needs of youngand elderly patients should also be recognized and supported,i.e. social security, job flexibility, rehabilitation, body image(including sexuality), home, and child care.

II. important ABC-related definitions

Guideline statements LoE Consensus

Visceral crisis is defined assevere organ dysfunction asassessed by signs andsymptoms, laboratorystudies, and rapidprogression of disease.Visceral crisis is not themere presence of visceralmetastases, but impliesimportant visceralcompromise leading to aclinical indication for amore rapidly efficacioustherapy, particularly sinceanother treatment optionat progression will probablynot be possible.

Expert opinion 95.0% (38) yes5.0% (2) abstain(40 voters)

Primary endocrine resistanceis defined as: a relapsewhile on the first 2 years ofadjuvant ET, or PD withinfirst 6 months of first-lineET for MBC, while on ETSecondary (acquired)endocrine resistance isdefined as: a relapse whileon adjuvant ET but afterthe first 2 years, or a relapsewithin 12 months ofcompleting adjuvant ET, orPD ≥6 months afterinitiating ET for MBC,while on ET.

Expert opinion 66.6% (22) Yes21.2% (7) abstain(33 voters)

LoE: available level of evidence; consensus: percentage of panelmembers in agreement with the statement; ET: endocrine therapy;PD: progressive disease; MBC: metastatic breast cancer.

Current terminology uses several ill-defined terms that oftenhave different meanings, leading to confusion and difficulty inadapting clinical trial findings to current practice populations.The ABC2 panel tried to define two of these important terms,

aiming at standardization of their use.Regarding endocrine resistance, an attempt was made to be

consistent with a definition reached by a number of investigatorsinvolved in breast cancer clinical trials, at a meeting sponsoredby NCI held in May 2012 and later approved by the NorthAmerican Breast Cancer Groups (NABCGs).It is also important to note that endocrine resistance is a con-

tinuum, and that strict definitions are mainly helpful for the clin-ical trial setting and not necessarily for routine clinical practice.

III. inoperable locally advanced,non-inflammatory, breast cancer

Guideline statements LoE Consensus

Before starting any therapy, acore biopsy providinghistology and biomarker (ER,PR, HER-2, andproliferation/grade)expression is indispensableto guide treatment decisions.

IB 97.2% (36) yes2.7% (1) abstain(37 voters)

Since LABC patients have asignificant risk of metastaticdisease, a full stagingworkup, including acomplete history, physicalexamination, laboratory tests,and imaging of chest andabdomen (preferably CTscans) and bone, prior toinitiation of systemictherapy, is highlyrecommended.

IB 100% (37) yes0% (0) abstain(37 voters)

PET–CT, if available, may beused (instead of and not ontop of CT scans and bonescan).

IIB 100% (37) yes0% (0) abstain(37 voters)

Systemic therapy (not surgeryor radiotherapy) should bethe initial treatment. If LABCremains inoperable aftersystemic therapy andeventual radiation, ‘palliative’mastectomy should not bedone, unless the surgery islikely to result in an overallimprovement in quality oflife.

Expertopinion

100% (40) yes0% (0) abstain(40 voters)

A combined treatmentmodality based on amultidisciplinary approach(systemic therapy, surgery,and radiotherapy) is strongly

IA 100% (39) yes0% (0) abstain(39 voters)

Continued

| Cardoso et al.

special article Annals of Oncology

by guest on September 19, 2014

http://annonc.oxfordjournals.org/D

ownloaded from

ConsensosobreCáncerdeMamaAgresivoHer2-enPrimeralíneadeQuimioterapia-Necesidaddedefiniresteperfildepacientes.- Enladecisiónterapeú-caesmuyrelevantelasintomatología.- Obje-voterapéu-co:RO,controldesíntomas- Cargatumoraly-empodeprogresióndelaenfermedad.

Cardoso 2014

Ø  50-60% responden a 1ª línea. Beneficio clínico “ EE o RO” más allá de 6m

Ø  Beneficio clínico previo, mejor predictor de eficacia.

Ø  25% son resistentes (RESISTENCIA PRIMARIA). Ø Recaída en los 1ºs 6 meses de M1 o en los primeros 2 años durante el tto adyuvante.

Ø M1 , prácticamente todos progresan al tto (RESISTENCIA SECUNDARIA).

RobertsonJFR,EurJCancer1997AgrawalA,etal.WorldJSurgOncol2006;4:40.Cardoso2014

Important ABC-related definitions

Current terminology uses several ill-defined terms that often havedifferent meanings, leading to confusion and difficulty in adaptingclinical trial findings to current practice populations.

The ABC2 Panel tried to define two of these important terms,aiming at standardization of their use.

Regarding endocrine resistance, an attempt was made to beconsistent with a definition reached by a number of investigatorsinvolved in breast cancer clinical trials, at a meeting sponsored byNCI held in May 2012 and later approved by the North AmericanBreast Cancer Groups (NABCG).

It is also important to note that endocrine resistance is a con-tinuum and that strict definitions are mainly helpful for the clinicaltrials setting and not necessarily for routine clinical practice.

Inoperable locally advanced, non-inflammatory, breast cancer

Inoperable locally advanced, inflammatory, breast cancer

LABC occurs at first presentation in about one fifth of breastcancer patients worldwide, with lower incidence in countries withestablished screening programs but as high as 60% in some othercountries [29]. Usually, the definition of LABC includes large oper-able primary breast tumours (stage IIB, IIIA) and/or those involving

Guideline statement LoE Consensus

VISCERAL CRISIS is defined as severe organdysfunction as assessed by signs andsymptoms, laboratory studies, and rapidprogression of disease. Visceral crisis is notthe mere presence of visceral metastases, butimplies important visceral compromiseleading to a clinical indication for a morerapidly efficacious therapy, particularly sinceanother treatment option at progression willprobably not be possible.

Expertopinion

95.0% (38) Yes5.0% (2)Abstain(40 voters)

PRIMARY ENDOCRINE RESISTANCE is definedas: relapse while on the first 2 years ofadjuvant ET, or PD within first 6 months of1st line ET for MBC, while on ET

SECONDARY (ACQUIRED) ENDOCRINERESISTANCE is defined as: relapse while onadjuvant ET but after the first 2 years, orrelapse within 12 months of completingadjuvant ET, or PD! 6months after initiatingET for MBC, while on ET.

Expertopinion

66.6% (22) Yes21.2% (7)Abstain(33 voters)

LoE: Available level of evidence; Consensus: Percentage of panel members inagreement with the statement; ET: endocrine therapy; PD: progressive disease;MBC: metastatic breast cancer.


Before starting any therapy, a core biopsyproviding histology and biomarker (ER, PR,HER-2, proliferation/grade) expression isindispensable to guide treatment decisions.

I B 97.2% (36) Yes2.7% (1) Abstain(37 voters)

Since LABC patients have a significant risk ofmetastatic disease, a full staging workup,including a complete history, physicalexamination, lab tests and imaging of chestand abdomen (preferably CT scans) and bone,prior to initiation of systemic therapy ishighly recommended.

I B 100% (37) Yes0% (0) Abstain(37 voters)

PET-CT, if available, may be used (instead of andnot on top of CT scans and bone scan).

II B 100% (37) Yes0% (0) Abstain(37 voters)

Systemic therapy (not surgery or radiotherapy)should be the initial treatment. If LABCremains inoperable after systemic therapyand eventual radiation, “palliative”mastectomy should not be done, unless thesurgery is likely to result in an overallimprovement in quality of life.

Expertopinion

100% (40) Yes0% (0) Abstain(40 voters)

I A

(continued )


A combined treatment modality based on amultidisciplinary approach (systemictherapy, surgery and radiotherapy) isstrongly indicated in the vast majority ofcases.

100% (39) Yes0% (0) Abstain(39 voters)

For TRIPLE NEGATIVE LABC, anthracycline- and-taxane-based chemotherapy isrecommended as initial treatment.

I A 85.3% (35) Yes9.7% (4) Abstain(41 voters)

For HER-2-POSITIVE LABC, concurrent taxaneand anti-HER-2 therapy is recommendedsince it increases the rate of pathologicalcomplete response (pCR).


For HER-2-POSITIVE LABC, anthracycline-basedchemotherapy should be incorporated in thetreatment regimen.


In HER-2-POSITIVE LABC, when ananthracycline is given, it should beadministered sequentially with the anti-HER-2 therapy.


Options for HORMONAL RECEPTOR POSITIVELABC include an anthracycline- and taxane-based chemotherapy regimen, or endocrinetherapy.

The choice of chemotherapy vs. endocrinetherapy, as initial treatment, will depend ontumour (grade, biomarker expression) andpatient (menopausal status, performancestatus, comorbidities, preference)considerations.


Following effective neoadjuvant systemictherapy with or without radiotherapy,surgery will be possible in many patients.This will consist of mastectomy with axillarydissection in the vast majority of cases, but inselected patients with a good response,breast conserving surgery may be possible.

II B 97.5% (39) Yes0% Abstain(40 voters)

LABC: locally advanced breast cancer; LoE: Available level of evidence; Consensus:Percentage of panel members in agreement with the statement; ER: oestrogen re-ceptor; PR: progesterone receptor.


For inflammatory LABC, overall treatmentrecommendations are similar to those fornon-inflammatory LABC, with systemictherapy as first treatment.


Mastectomy with axillary dissection isrecommended in almost all cases, even whenthere is good response to primary systemictherapy.


Immediate reconstruction is generally notrecommended in patients with inflammatoryLABC.

Expertopinion

94.7% (36) Yes2.6% (1) Abstain(38 voters)

Loco-regional radiotherapy (chest wall andlymph nodes) is required, even when a pCR isachieved with systemic therapy.


MBC: metastatic breast cancer; LoE: Available level of evidence; Consensus: Per-centage of panel members in agreement with the statement; pCR: pathologicalcomplete remission.

F. Cardoso et al. / The Breast xxx (2014) 489e502492

TERAPIAS DIRIGIDAS EN TUMORES LUMINALES TIPOS DE HORMONOTERAPIA

Año Hormonoterapia Mecanismo de acción

1977 SERMs Tamoxifeno Toremifeno

Antagonistas del RE en el tejido mamario

1990 IA Anastrozol Exemestano Letrozol

Inhiben la síntesis de estrógenos en mujeres postmenopáusicas.

2000 SERDs Fulvestrant

Se une al RE, impide su dimerización y acelera su degradación.

TERAPIAS DIRIGIDAS EN TUMORES LUMINALES HORMONOTERAPIA CMM: RESULTADOS EC 1ªL CMM FASE III/ FASE II

•  IA 3ª G frente a TAMOXIFENO •  >TP con IA ( 9,5 m-10,5 m// 15-16 m con Letrozol) •  No diferencias en SG en los EC individuales •  Ventaja en SG en un meta-análisis

•  FULVESTRANT •  F 250 similar a TAMOXIFENO •  F 500 vs ANASTROZOL

•  FIRST- FII R: •  >TP (23.4 vs 13.1 m; HR: 0.66; 95% CI: 0.47-0.92; p = .01) •  >SG (54.1 vs 48.4 m; HR: 0.70; 95% CI: 0.50-0.98; p = .0411)

•  EC FALCON F III ???

•  FULVESTRANT + ANASTROZOL vs ANASTROZOL •  EC FACT: No diferencias en SLP ni en SG. •  SWOG: > TP y > SG con F+A .

Naboltz EJC 2003; Mouridsen JCO 2003; Paridaens JCO 2008; Mauri JNCI 2006; 8 Howell JCO 2004; Robertson BCRT 2012; Robertson SABC 2014 Bergh JCO 2012; Mehta NEJM 2012.

UpdatedTTPanalysis69%ofpa-entshadprogressed*

Fullanalysisset,n=205

0 6 12 18 24 30 36 42 48 0.0

0.2

0.4

0.6

0.8

1.0 Pr

opor

tion

of p

atie

nts

aliv

e a

nd p

rogr

essi

on-fr

ee

Time (months) 102 74 65 52 45 34 20 6 0 103 69 55 39 30 21 8 2 0

Fulvestrant 500 mg Anastrozole 1 mg

HR=0.66 95% CI (0.47, 0.92)

p=0.01

Fulvestrant 500 mg Anastrozole 1 mg

Number of patients at risk: 0 12 18 42 48 Months 36 30 24 6

*After primary DCO, progression was determined by investigator opinion

Fulvestrant 500 mg n=102

Anastrozole 1 mg n=103

Number of progressions (%) 63 (61.8) 79 (76.7)

Median (months) 23.4 13.1

Robertson JFR et al. Br Can Res Treat 2012; 136:503–511

SG: 54 m vs 48 m HR: 0,70

¿ Cuándo pasar de Terapia Endocrina a Quimioterapia?

LTD,lifethreateningdisease;PD,progressivedisease.

1.CardosoF,etal.TheBreast2014;23:489–502;2.PartridgeAH,etal.JClinOncol2014;32:3307–3329.

1st-line endocrine therapy

2nd-line

endocrine therapy

3rd-line

endocrine therapy

Chemotherapy

LTD LTD LTD

PD PD

“Chemotherapy should be reserved for cases of rapidly progressive disease or proven endocrine-resistance.” – ESMO/ABC2 guidelines1

“Endocrine therapy, rather than chemotherapy… except for immediately life

threatening disease or if there is concern regarding endocrine resistance.” – ASCO guidelines2

BENEFICIOCLINICO6MESES

2ªs Líneas de Terapia endocrina en estudios fase III LETROZ EXEM FULVBD

(EFFECT)FULVADCONFIRM

EXEM+EVEROLIMBOLERO

FULVAD+PALBOPALOMA-2

Control Ac.Megest

Ac.Megest

Exemestan FULVBD

Exemes FVAD

PFS 3,8m 4,8m 3,7m 6,5m 7,8/11m 9,2mHR 1,04 0,82 0,96 0,80 0,43 0,42p NS 0,037 NS 0,006 <0.0001 <0.0001

Chia JCO 2008; Johnston Lancet Oncol 2013; Di Leo JNCI 2014 Baselga J et al, New Engl J Med 2012 Finn Lan Oncol 2015

• FULVESTRANT + ANAST vs FULV-PLACEBO vs EXEMESTANO (SOFEA) •  No diferencias en TP ni en SG.

Nature Reviews | Cancer

ER pathwayr Loss of ER expressionr ESR1 mutation,CORNKȮECVKQPQT�VTCPUNQECVKQP

r Aberrant expressionor mutation of EREQ�TGIWNCVQTU

Secondary messengersr PI3K pathway G�I��OWVCVKQPU�KP�PIK3CA, PTEN and AKT1)

r MAPK pathway

Growth factor receptor pathwayHER2, IGF1R and EGFR overexpression,mutation orCORNKȮECVKQP

Tumour microenvironmentr�'%/��ȮDTQPGEVKP��EQNNCIGPr�%GNNWNCT�EQORQPGPVU��6#/�

(M1, M2), CAF, MSC, MDSC, 6H��EGNN��6H��EGNN��$�EGNN��FGPFTKVKE�EGNN��0-�EGNN��E[VQVQZKE�6�EGNN��QUVGQENCUV��osteoblast and platelet

EMT and CSCr�0QVEJ��*GFIGJQI��906�CPF�69+56�

r�6WOQWT�FQTOCPE[��

Cell cycle machineryr�.QUU�QH�4$��R��CPF�R��r�#ORNKȮECVKQP�

of CCND1

AI resistanceApoptosis and senescencer Mutation of TP53r�#ORNKȮECVKQP�QH�MDM2r ↑ $%.��CPF�UWTXKXKPr ↑ 6GNQOGTCUG

1. Beatson, G. T. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet 33, 108–121 (1983).This paper is the starting place for any discussion of endocrine therapy and reminds us how instructive case reports can be: the genomic analysis of extreme responders to targeted therapy is a modern iteration of this theme.

2. Lin, N. U. & Winer, E. P. Advances in adjuvant endocrine therapy for postmenopausal women. J. Clin. Oncol. 26, 798–805 (2008).

3. Pagani, O. et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. New Engl. J. Med. 371, 107–118 (2014).This is a well-powered study showing a benefit for the AI exemestane versus tamoxifen in combination with ovarian suppression. Further follow-up will be required to demonstrate the full magnitude of the advantage of AIs in this setting.

4. Di Leo, A. et al. Final overall survival: fulvestrant 500 mg versus 250 mg in the randomized CONFIRM trial. J. Natl Cancer Inst. 106, djt337 (2014).

5. Robertson, J. F. R. et al. Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: overall survival from the phase II ‘first’ study. Abstracts from the 37th Annual SABCS S6-04 (2014).

6. Early Breast Cancer Trialists’ Collaborative Group. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378, 771–784 (2011).

7. Mauri, D., Pavlidis, N., Polyzos, N. P. & Ioannidis, J. P. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J. Natl Cancer Inst. 98, 1285–1291 (2006).

8. Ellis, M. Overcoming endocrine therapy resistance by signal transduction inhibition. Oncologist 9, 20–26 (2004).

9. Ellis, M. J. et al. Lower-dose versus high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA 302, 774–780 (2009).This is a study in the modern era of oestradiol for AI-resistant breast cancer showing that the lower

dose (6 mg) is safer, better tolerated and as effective as the traditional high-dose approach.

10. Ellis, M. J. et al. Z1031B neoadjuvant aromatase inhibitor trial: a phase 2 study of triage to chemotherapy based on 2 to 4 week Ki67 level >10%. Cancer Res. 72, PD07-01 (2012).

11. Zanotti, L., Bottini, A., Rossi, C., Generali, D. & Cappelletti, M. R. Diagnostic tests based on gene expression profile in breast cancer: from background to clinical use. Tumor Biol. 35, 8461–8470 (2014).

12. Kiyotani, K., Mushiroda, T., Nakamura, Y. & Zembutsu, H. Pharmacogenomics of tamoxifen: roles of drug metabolizing enzymes and transporters. Drug Metab. Pharmacokinet. 27, 122–131 (2012).

13. Ding, L. et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464, 999–1005 (2010).

14. Shah, S. P. et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461, 809–813 (2009).This is the first paper to document, using next-generation DNA sequencing, the evolution of mutations over time as ER+ breast cancer progresses.

Tumour dormancy and disseminated tumour cellsTumour dormancy is defined as the state of microscopic non-progressing metastases that remain capable of pro-gression to overt advanced disease after a long period of time. The natural history of ER+ breast cancer indicates that micro-metastatic ER+ cancer cells are in a reversible dormant state and the long-term efficacy of endocrine therapy, including AI therapy, involves the maintenance of the dormant state rather than the induction of cell death or irreversible cell cycle arrest171,172. Reactivation of cancer cell

Figure 8 | The hallmarks of AI resistance. Several cell-autonomous and non-cell-autonomous mechanisms in oestrogen receptor-positive (ER+) breast cancer and the tumour microenvironment could lead to aromatase inhibitor (AI) resistance. These include deregulation of the ER pathway, growth factor receptor signalling, secondary messengers, the cell cycle machinery, apoptosis and senescence, epithelial-to-mesenchymal VTCPUKVKQP�'/6��CPF�ECPEGT�UVGO�EGNNU�%5%U��VWOQWT�FQTOCPE[��CPF�VJG�VWOQWT�microenvironment. CAF, cancer-associated fibroblast; CCND1��E[ENKP�&��'%/��extracellular matrix; EGFR, epidermal growth factor receptor; IGF1R, insulin-like growth HCEVQT��TGEGRVQT��/&5%��O[GNQKF�FGTKXGF�UWRRTGUUQT�EGNN��/5%��OGUGPEJ[OCN�UVGO�EGNN��0-�EGNN��PCVWTCN�MKNNGT�EGNN��6#/��VWOQWT�CUUQEKCVGF�OCETQRJCIG��6

H, T helper.

growth could be due to cancer cell-intrinsic mechanisms such as the acquisition of resistance mutations; however, the cell biological mechanisms that are responsible for the loss of tumour dormancy and cancer reactivation are poorly understood. Evidence suggests that the bone mar-row is a potential sanctuary site where cancer cells reside in the haematopoietic stem cell niche, protected from treat-ment by the biologically active molecules that are produced there173. It has long been recognized that disseminated tumour cells (DTCs) are present in the bone marrow in 30% of patients with localized or early-stage breast can-cer174, and these patients are at a higher risk of both skel-etal and extraskeletal metastasis175. These DTCs can persist in the bone marrow for years in a quiescent state and are resistant to cancer therapies176. Some DTCs have CSC fea-tures with high expression of SNAIL, a transcription fac-tor involved in EMT induction177. Interventions that alter bone physiology, such as bisphosphonates, clearly have the potential to favourably alter the natural history of DTCs in the bone marrow, at least in postmenopausal women178.

ConclusionsThe FDA approvals for the delay in tumour progression achieved by everolimus and the CDK4 and CDK6 inhibi-tor palbociclib in combination with an AI promote opti-mism that considerable improvements in the treatment of AI therapy-resistant ER+ breast cancer are a near-term possibility. However, there is currently no evidence to date that these dual-targeting approaches improve overall survival or are active adjuvant treatments. Improvements in the fidelity of preclinical models are therefore essen-tial, and PDX models clearly have a role in moving the endocrine resistance field beyond the restricted discov-ery space afforded by the few ER+ cell lines available31. However, the value of PDX models for the study of tumour dormancy, stem cell-like behaviour and stro-mal–epithelial interactions is unclear. Nonetheless, PDX studies, paired with data from the omics analysis of clini-cal samples, should instruct the design of trials of more effective multi-agent combinations, individually tailored to resistance mechanisms diagnosed through sequencing or other omics techniques (FIG. 8).

REVIEWS

272 | MAY 2015 | VOLUME 15 www.nature.com/reviews/cancer

© 2015 Macmillan Publishers Limited. All rights reserved

Ma CX et al. Nat Reviews 2015

Mecanismos de Resistencia tras IA

PI3K

AKT

PTEN

mTOR

RAS

RAF

MEK

MAPK

ERtargetgenetranscrip-on

P P

EGFRHER2

E

E

ERE

TKI

PI3/AKT/MtorInhibitorsEverolimus

AromataseInhibitorNonsteroidalAIs

AnastrozoleLetrozole

SteroidalAIsExemestane

Selec-veEstrogenReceptorModulatorsTamoxifenToremifene

ERDownregulatorFulvestrant

HDACInhibitorEn-nostat

¿ COMO REVERTIR ESA RESISTENCIA? Combinación terapia antiestrogénica+ terapia

dirigida en tumores RE+

CDK4/6InhibitorPD0332991LEE011ABEMACICLIB Cell

Cycle

Transcription Silencing

ERE

ERE

SRC inhibitor Dasatinib

SRC

Austreid 2014, Ma CX et al. Nat Reviews 2015

Receptor Tyrosine Kinase

PI3K

P P P

P

P P

P P

mTORC2

mTORC1 S6K

AKT

IRS1

Growth factors

TSC

PTEN

1)Ac8vacióndePI3K:InhibidoresdelavíaPI3K/AKT/mTOR

mTORC2

EVEROLIMUS

BKM120Buparlisib

BYL719Alpelisib

α-specific PI3K inhibitor

Pan Class I PI3K inhibitor of all four class I PI3K

isoforms (α, β, γ, δ)

4EBP1

• vía + frec activada en la señalización del cáncer. •  crecimiento tumoral y resistencia a ttos antitumorales. •  disrupción de la vía en PI3K

•  mutaciones o amplificaciones •  pérdida de PTEN •  alteraciones en los R factores de crecimiento. •  Cross-talk con otros vías ((RE).

Crecimiento tumoral, supervivencia, angiogénesis, metabolismo, proliferación

mTOR inhibitor

ESTUDIOBOLERO-2

RESULTS

METHODS

OBJECTIVE

INTRODUCTION

BOLERO-2: Efficacy and Safety of Everolimus Plus Exemestane in Patients With Advanced

Invasive Lobular Carcinoma Thomas Bachelot,1 Shinzaburo Noguchi,2 Ines Deleu,3 Patrick Neven,4 Puttisak Puttawibul,5

Daniel Y C Heng,6 Thomas Brechenmacher,7 Francois Ringeisen,8 Stephen Saletan,9 and Gabriel Hortobagyi10

1Département de Cancérologie Médicale, Centre Léon Bérard, Lyon, France; 2Osaka University, Osaka, Japan; 3Oncologic Centre, AZ Nikolaas, Sint-Niklaas, Belgium; 4UZ Leuven, Leuven, Belgium; 5Songklanagarind Hospital, Prince of Songkla University, Songkhla, Thailand; 6University of Calgary, Tom Baker Cancer Centre, Calgary, Alberta, Canada;

7Novartis Pharma S.A.S., Rueil-Malmaison, France; 8Novartis Pharma AG, Basel, Switzerland; 9Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; 10The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

• Invasive lobular carcinoma (ILC) is less common than infiltrating ductal carcinoma (IDC), and accounts for 8% to 14% of all breast cancers.1

• Lobular carcinomas have more favorable clinicopathological parameters compared with IDC tumors, such as hormone-receptor positivity (HR+), nonamplification of HER2 (HER2–), low histological grade, and low proliferative index.2

– However, lobular carcinomas have an increased propensity for multifocal and multicentric distribution and for bilaterality and different patterns of metastatic involvement compared with IDC (e.g., lower incidence of lung/pleural and central nervous system metastases and higher incidence of ovarian, gastrointestinal, and nodal involvement)1

– Thus, despite the favorable clinicopathological characteristics, survival prognosis is generally worse in patients with ILC1,2

• Endocrine therapy is the mainstay of treatment for patients with HR+ advanced breast cancer. – However, disease progression eventually occurs, and the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of

rapamycin (mTOR) signaling pathway is thought to be a key pathway involved in breast cancer progression3

– Next-generation sequencing of archival tumor samples (n=227) suggests that the PI3K/AKT/mTOR pathway was altered in more than half the patients4

• Consistent with this rationale, the BOLERO-2 Phase III study demonstrated the efficacy and safety of combining mTOR inhibition (everolimus [EVE]) with endocrine therapy (the steroidal aromatase inhibitor exemestane [EXE]) in postmenopausal women with HR+ advanced breast cancer progressing after nonsteroidal aromatase inhibitors (NSAIs; letrozole or anastrozole).5-7

– EVE+EXE more than doubled the median progression-free survival (PFS) versus placebo (PBO) + EXE (7.8 months vs 3.2 months, respectively; hazard ratio [HR]=0.45; 95% confidence interval [CI], 0.38–0.54; p<0.0001) without compromising health-related quality of life7

– Analysis by central assessment confirmed the PFS benefit (11.0 months for EVE+EXE vs 4.1 months for PBO+EXE; HR=0.38 [95% CI, 0.31–0.48]; log-rank p<0.0001)

• This exploratory analysis of BOLERO-2 examines the efficacy and safety of EVE+EXE in the subgroup of patients with ILC compared with the overall study population.

Baseline Characteristics

Overall BOLERO-2 Population• A total of 724 patients from 24 countries were randomly assigned to EVE+EXE (n=485) or PBO+EXE (n=239) from

June 2009 to January 2011.• Patient baseline characteristics were well balanced between treatment arms (previously reported).6,7

• Median age was 61 years, 59% of patients had visceral involvement, and 77% had bone metastases.

Subset of Patients With ILC• At baseline, 104 patients (14%) of the overall randomized population had ILC (64 patients [13%] assigned to EVE+EXE

and 40 patients [17%] assigned to PBO+EXE).• Patient baseline characteristics were well balanced between treatment arms in this patient subset (Table 1). – Women with ILC had a different distribution of metastases compared with the overall BOLERO-2 population,7 although the

proportion of patients with 3 or more metastatic sites at baseline was comparable (29% vs 37%) • The proportion of ILC patients with visceral metastases was lower compared with the overall BOLERO-2 population7

(36% vs 59%) • The proportion of ILC patients with bone metastases was higher compared with the overall BOLERO-2 population7

(91% vs 77%)

Most Common AEs in Patients With ILC • The most common AEs (t25% among patients receiving EVE+EXE) included stomatitis (50%), diarrhea (41%), nausea (36%),

fatigue (34%), and rash (33%) (Table 2). – The most common grade 3/4 AEs observed with EVE+EXE included stomatitis (6%), diarrhea (6%), fatigue (5%),

decreased appetite (5%), and hyperglycemia (5%) – These are consistent with the most common AEs reported in the overall BOLERO-2 population7

• Pneumonitis and interstitial lung disease were observed in the EVE arm, but not in the PBO arm; most events were low grade.

PFS in Patients With ILC • EVE+EXE improved PFS versus PBO+EXE (6.9 months vs 4.2 months, respectively; HR=0.59; 95% CI, 0.37–0.95;

local assessment) in patients with ILC (Figure 2A). – The PFS improvement with EVE+EXE versus PBO+EXE in patients with ILC was confirmed by central assessment

(15.4 months vs 5.6 months, respectively; HR=0.45; 95% CI, 0.24–0.87; Figure 2B) – Median PFS was longer based on disease assessment by central reviewers, potentially due to the smaller proportion of

adjudicated events in both treatment arms during central review compared with local assessment

Table 1. Baseline Characteristics of Patients*

Characteristic

ILC Population Full Analysis Population

EVE+EXE (n=64)

PBO+EXE (n=40)

EVE+EXE (n=485)

PBO+EXE (n=239)

Median age, years (range) 63 (40–83) 64 (45–79) 62 (34–93) 61 (28–90)

Race, %

Caucasian 88 95 74 78

Asian 9 5 20 19

Black 2 0 3 1

Other 2 0 3 2

ECOG performance status, %

0 56 70 60 59

1 44 30 36 35

2 0 0 2 3

Metastatic site of cancer, %

Visceral (excluding CNS) 36 35 58 59

Lung 8 13 30 33

Liver 23 23 33 30

Bone 88 98 77 77

Previous tamoxifen, % 44 50 47 50

Previous fulvestrant, % 17 10 17 16

Previous chemotherapy, % 69 60 69 65

Number of prior therapies,† %

1 or 2 47 55 46 47

t3 53 45 54 53

*Rounded to whole numbers from calculated percentages; may introduce small discrepancies from summary percentages in text †Includes patients who also received neoadjuvant therapy Abbreviations: CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; EVE, everolimus; EXE, exemestane; ILC, invasive lobular carcinoma; PBO, placebo

Table 2. Most Common Treatment-Emergent Adverse Events (Reported in �25% of Patients Receiving EVE+EXE) in Patients With ILC at Baseline*

EVE+EXE (n=64), % PBO+EXE (n=40), %Grade Grade

AE (Preferred Term) All 1 2 3 4 All 1 2 3 4Stomatitis 50 22 22 6 0 5 5 0 0 0Diarrhea 41 30 5 5 2 18 10 8 0 0Nausea 36 17 17 0 2 30 20 10 0 0Fatigue 34 17 13 5 0 33 15 15 3 0Rash 33 23 8 2 0 8 5 3 0 0Epistaxis 27 25 2 0 0 3 3 0 0 0Decreased appetite 25 14 6 5 0 15 8 5 3 0Weight decreased 28 13 16 0 0 10 3 8 0 0Pneumonitis† 22 9 11 2 0 0 0 0 0 0Hyperglycemia† 20 9 6 5 0 0 0 0 0 0

*Rounded to whole numbers from calculated percentages; may introduce small discrepancies from summary percentages in text †Incidence <25%, but AE of special interest Abbreviations: AE, adverse event; EVE, everolimus; EXE, exemestane; ILC, invasive lobular carcinoma; PBO, placebo

Study Design and Treatment• Multicenter, double-blind, randomized, PBO-controlled, international, Phase III study (Figure 1).5,6

• Patients were randomly assigned in a 2:1 ratio to receive either EVE or matching PBO in a blinded manner, in addition to open-label EXE.

• Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal.• No crossover was allowed after disease progression.

Endpoints• PFS was the primary endpoint. – Time from randomization to first documented progression or death from any cause – Evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 based on investigator assessment

(local radiologic assessment, primary endpoint) • Adverse events (AEs) were monitored continuously throughout the study and graded according to the National Cancer

Institute Common Terminology Criteria for Adverse Events, version 3.0.6

Statistical Methods• Exploratory analysis of patients with ILC at the data cutoff for the final PFS analysis (18-month median follow-up).• PFS was assessed by Kaplan-Meier analyses; HRs and 95% CIs were determined using an unstratified Cox model.

Abbreviations: BC, breast cancer; CBR, clinical benefit rate; ER+, estrogen-receptor–positive; HER2–, human epidermal growth factor receptor-2–negative; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; QOL, quality of life; R, randomization

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; ILC, invasive lobular carcinoma; PBO, placebo; PFS, progression-free survival

• Evaluate the efficacy and safety of EVE+EXE in the subgroup of patients with ILC versus the overall BOLERO-2 population.

• The combination of EVE+EXE more than doubled PFS in patients with HR+, HER2– advanced breast cancer who recurred/progressed during/after NSAIs.

– Improvement in PFS in the ILC subset was consistent with the PFS benefit observed in the overall BOLERO-2 population

• Local assessment: median PFS, 6.9 months versus 4.2 months, respectively; HR=0.59; 95% CI, 0.37–0.95 in the ILC subset compared with 7.8 versus 3.2 months, respectively; HR=0.45; 95% CI, 0.38–0.54 in the overall BOLERO-2 population

• Central assessment: median PFS, 15.4 months versus 5.6 months, respectively; HR=0.45; 95% CI, 0.24–0.87 in the ILC subset compared with 11.0 months versus 4.1 months, respectively; HR=0.38; 95% CI, 0.31–0.48 in the overall BOLERO-2 population

• The exploratory analysis suggests that EVE+EXE is an effective treatment option in patients with HR+, HER2– advanced breast cancer with lobular histology.

CONCLUSIONS

References1. Arpino G et al. Breast Cancer Res 2004;6(3):R149–156.2. Korhonen T et al. Breast 2013;22(6):1119–1124.3. Miller TW et al. J Clin Invest 2010;120(7):2406–2413.4. Hortobagyi G et al. J Clin Oncol 2013;31(Suppl):abstr LBA509.5. http://www.clinicaltrials.gov/ct2/show/NCT00863655?term=NCT00863655&rank=1. Accessed 10 February 2014.6. Baselga J et al. N Engl J Med 2012;366(6):520–529.7. Yardley DA et al. Adv Ther 2013;30(10):870–884.

Abstract 448

N=724Everolimus 10 mg/d

+Exemestane 25 mg/d (n=485)

Placebo+

Exemestane 25 mg/d (n=239)

7098 figure 1 draft 1.1This tagline is for information only;

DO NOT PRINT

• Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease • No crossover

• Primary: PFS (local assessment)• Secondary: OS, ORR, CBR, QOL, safety, bone markers, PK

Endpoints

• Postmenopausal ER+ HER2–

• Unresectable locally advanced or metastatic BC • Recurrence or progression after letrozole or anastrozole

R2:1

0

0.2

0.4

0.6

0.8

1.0

Time (weeks)0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90

EVEPBO

Number of Patients at Risk

EVEPBO

Number of Patients at Risk

64 56 49 36 30 29 22 21 18 17 11 7 6 5 4 040 32 25 20 13 12 8 8 6 5 2 2 1 1 0 0

HR=0.5995% CI, 0.37–0.95

EVE 10 mg + EXE: 6.93 monthsPBO+EXE: 4.17 months

Kaplan-Meier medians

HR=0.4595% CI, 0.24–0.87

EVE 10 mg + EXE: 15.44 monthsPBO+EXE: 5.62 months

Kaplan-Meier medians

EVE 10 mg + EXE (n/N = 42/64)PBO+EXE (n/N = 32/40)

Censoring times

Prob

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ty o

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-Fre

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ility

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rogr

essi

on-F

ree

Surv

ival

EVE 10 mg + EXE (n/N = 20/64)PBO+EXE (n/N = 18/40)

Censoring times

7098 Figure 2 draft 1.2This tagline is for information only;

DO NOT PRINT

a)

b)

0

0.2

0.4

0.6

0.8

1.0

Time (weeks)0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90

64 52 43 33 28 26 18 18 16 15 10 7 5 4 3 040 28 21 16 10 7 6 6 4 4 2 2 1 1 0 0

Figure 1. BOLERO-2 Trial Design

Figure 2. Kaplan-Meier Analysis of PFS in Patients With ILC at Baseline by (a) Investigator Review or (b) Central Review

Scan this QR code

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IS A MINIMUM OF 4”X4” ON FINAL PRINT; 8“X8” OR LARGER IS PREFERABLE

Presented at EBCC-9, Glasgow, Scotland, 19–21 March 2014. This study was sponsored by Novartis Pharma AG.

Baselga J et al, New Engl J Med 2012

1.0

0.8

0.6

Prob

abili

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f Pr

ogre

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n-Fr

ee S

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val

0.4

0.2

0 26 24 22 20 18 16 14

Time (months) 12 10 8 6 4 2 0

0 0

3 0

10 0

12 0

19 0

37 5

56 8

86 13

130 21

175 33

221 48

309 82

389 132

485 239

EVE+EXE PBO+EXE No. at risk

HR = 0.38 (95% CI, 0.31-0.48) Log-rank P < .0001 Kaplan-Meier medians EVE+EXE: 11.0 months PBO+EXE: 4.1 months

Censoring times EVE+EXE (n/N = 188/485) PBO+EXE (n/N = 132/239)

ORIGINAL RESEARCH

Everolimus Plus Exemestane in PostmenopausalPatients with HR+ Breast Cancer: BOLERO-2 FinalProgression-Free Survival Analysis

Denise A. Yardley • Shinzaburo Noguchi • Kathleen I. Pritchard • Howard A. Burris III • Jose Baselga •

Michael Gnant • Gabriel N. Hortobagyi • Mario Campone • Barbara Pistilli • Martine Piccart •

Bohuslav Melichar • Katarina Petrakova • Francis P. Arena • Frans Erdkamp • Wael A. Harb •

Wentao Feng • Ayelet Cahana • Tetiana Taran • David Lebwohl • Hope S. Rugo

To view enhanced content go to www.advancesintherapy.comReceived: September 18, 2013 / Published online: October 25, 2013! The Author(s) 2013. This article is published with open access at Springerlink.com

ABSTRACT

Introduction: Effective treatments for

hormone-receptor-positive (HR?) breast cancer

(BC) following relapse/progression on

nonsteroidal aromatase inhibitor (NSAI)

therapy are needed. Initial Breast Cancer Trials

of OraL EveROlimus-2 (BOLERO-2) trial data

demonstrated that everolimus and exemestane

significantly prolonged progression-free

survival (PFS) versus placebo plus exemestane

alone in this patient population.

Methods: BOLERO-2 is a phase 3, double-blind,

randomized, international trial comparing

everolimus (10 mg/day) plus exemestane

(25 mg/day) versus placebo plus exemestane in

postmenopausal women with HR? advanced BC

with recurrence/progression during or after

Portions of the data have been presented previously:Piccart-Gebhart MJ, Noguchi S, Pritchard KI, Burris HA,Rugo HS, Gnant M, et al. Everolimus for postmenopausalwomen with advanced breast cancer: Updated results ofthe BOLERO-2 phase III trial [abstract]. Presented at the48th Annual Meeting of the American Society of ClinicalOncology; June 1–5, 2012; Chicago, IL. Abstract 559.

Electronic supplementary material The onlineversion of this article (doi:10.1007/s12325-013-0060-1)contains supplementary material, which is available toauthorized users.

D. A. Yardley (&) ! H. A. Burris IIISarah Cannon Research Institute and TennesseeOncology, PLLC, Nashville, TN 37203, USAe-mail: [email protected]

S. NoguchiDepartment of Breast and Endocrine Surgery, OsakaUniversity, Suita, Osaka 565-0871, Japan

K. I. PritchardSunnybrook Odette Cancer Centre and theUniversity of Toronto, Toronto, ON M4N 3M5,Canada

J. BaselgaMemorial Sloan-Kettering Cancer Center, New York,NY 10065, USA

M. GnantDepartment of Surgery, Comprehensive CancerCenter, Medical University of Vienna, 1090 Vienna,Austria

G. N. HortobagyiThe University of Texas MD Anderson CancerCenter, Houston, TX 77030, USA

M. CamponeInstitut de Cancerologie de l’Ouest, ReneGauducheau, Centre de Recherche en Cancerologie,44805 Nantes Saint Herblain, France

Enhanced content for Advances in Therapyarticles is available on the journal web site:www.advancesintherapy.com

123

Adv Ther (2013) 30:870–884DOI 10.1007/s12325-013-0060-1

Yardley. ADV Ther 2013

PFS por Local Assessment: 7,8 m

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BELLE-2:Fulvestrant±BuparlisibPhaseIIIStudyinHR+/HER2–ABC:AIResistantandmTORiNaive

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Baselga J et al. SABCS 2015

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Beneficio en mutaciones con ctDNA PIK3CA mutations

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22/3/15 11:49The Nobel Prize in Physiology or Medicine 2001

Página 1 de 2http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/illpres/index.html

The Nobel Prize in Physiology or Medicine 2001

The Nobel Prize inPhysiology orMedicine 2001The Nobel Assembly at Karolinska Institutethas awarded the Nobel Prize in Physiology orMedicine jointly to Leland Hartwell, Tim Huntand Paul Nurse for their discoveries of "keyregulators of the cell cycle". Using genetic andbiochemical methods, they identified themolecules CDK and cyclin that control the cellcycle in eukaryotic organisms. Thesefundamental discoveries have a profoundimpact on many aspects of biology andmedicine.

CDK and cyclin are key molecules that control andcoordinate DNA-synthesis, chromosome separationand cell division. CDK and cyclin together drive thecell from one cell cycle phase to the next.

Contents:

| The Nobel Prize in Physiology or Medicine 2001 | Introduction | Leland Hartwell | Paul Nurse | Tim Hunt | The Implications of the Discoveries |

Play the "Control of the Cell Cycle" game!

Based on materials from the 2001 Nobel Poster for Physiology or MedicineCredits

Nobel Poster from the Nobel Committee for Physiology or Medicine, web adapted by Nobel Web

7

Rb as Master-Regulator of the R-point

7

palbociclib

PFIZER CONFIDENTIAL

F.II-PALOMA-1/TRIO-18StudyDesign(NCT00721409):1ªLINEA:hormonosensibles

•  Randomizedphase2open-labeltrialinvolving50centersin12countries

•  Keyeligibilitycriteria:inoperableER-posi-ve/HER2-nega-velocallyrecurrentdisease,postmenopausalstatus,nopriortherapyforadvancedbreastcancer,nopriorCDKinhibitors,noletrozolewithin12months,noprior/currentbrainmetastases,measurabledisease(RECIST1.0)orbone-onlydisease,ECOGperformancestatus≤1,adequatebonemarrowandrenalfunc-on

Finnetal.LancetOncol.E-pubDec16,2014

Palbociclib 125 mg/d† +

Letrozole 2.5 mg/d

Letrozole 2.5 mg/d

ER+/HER2− advanced

breast cancer

*Randomization stratified by disease site and disease-free interval. † Palbociclib schedule 3/1 (28-day cycles).

1:1

RANDOMIZATION*

Palbociclib 125 mg/d† +

Letrozole 2.5 mg/d

Letrozole 2.5 mg/d

ER+/HER2− advanced

breast cancer with CCND1 amplification and/or loss of

p16

1:1

n=66 n=99

RANDOMIZATION*

Cohort 1 Cohort 2

TERAPIAS DIRIGIDAS EN TUMORES LUMINALES EC FII R PALOMA 1-TRIO18: SLP y SG

Articles

www.thelancet.com/oncology Vol 16 January 2015 29

objective response (by RECIST version 1.0), clinical benefi t (as defi ned by the sum of complete plus partial responses and stable disease for 24 weeks or more), duration of response, and overall survival. Additional secondary endpoints were safety and tissue and serum biomarker analyses. Finally, we also assessed patient-reported outcomes using the modifi ed Brief Pain Inventory (Short Form; mBPI-sf) done on day 1 of each treatment cycle; the mBPI-sf was used to capture whether palbociclib adds to the commonly reported adverse event seen with aromatase inhibitors (myalgias and joint pain).

Statistical analysisWe used a two-part study design (ie, two sequential cohorts) to allow us to assess both the activity of the palbociclib plus letrozole combination and to determine whether further patient selection on the basis of additional biomarkers (CCND1 or p16) was warranted. We planned to enrol 60 patients (30 per treatment group) into cohort 1 to provide initial safety and effi cacy (progression-free survival) data in patients with oestrogen receptor-positive, HER2-negative, advanced breast cancer. In cohort 2, we planned to include 150 patients (75 per treatment group) who also had CCND1 gene amplifi cation or loss of p16. Cohort 1 was intended to be an exploratory analysis, and the analysis of the primary endpoint was initially intended to be based on cohort 2 only. Assuming 114 progression-free survival events in cohort 2 and using a one-sided α of 0·10, a sample size of 150 would have 80% power to detect an HR of 0·67 (palbociclib plus letrozole vs letrozole alone), including one futility interim analysis. This HR would represent a median progression-free survival of 9 months in the control group and 13·5 months in the experimental group.13

However, an unplanned interim analysis of cohort 1 based on 31 progression-free survival events was done when we noted that almost twice as many patients in the control group were coming off the study because of disease progression. This interim analysis showed clinically meaningful activity of the palbociclib plus letrozole combination compared with letrozole alone (HR 0·35, 95% CI 0·170·72, p=0·006). These preliminary results from cohort 1 also suggested that further patient selection based on CCND1 amplifi cation or p16 loss was unlikely to further improve patient outcome over the use of oestrogen receptor and HER2 status alone (HR with CCND1 or p16 copy changes 0·37 [95% CI 0·10–1·40; p=0·13] vs HR with no CCND1 or p16 copy changes 0·19 [0·05–0·67; p=0·0045]). As a result, we stopped further enrolment into cohort 2 and amended the statistical analysis plan such that the primary endpoint would be analysed in cohorts 1 and 2 combined instead of cohort 2 alone. These study changes were made prospectively without any effi cacy results from cohort 2 and were

Figure 2: Progression-free survival (intention-to-treat population)HR=hazard ratio.

0

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363220 2412 160 284 8 40

363220 2412 160 284 8 40

363220 2412 160 284 8 40

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Cohort 2

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Letrozole51

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83

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Palbociclib plus letrozoleLetrozole

HR 0·488 (95% CI 0·319–0·748; one-sided p=0·0004)

HR 0·299 (95% CI 0·156–0·572; one-sided p<0·0001)

HR 0·508 (95% CI 0·303–0·853; one-sided p=0·0046)


Letrozole1510

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2920

2114

5049

54133

3726

Articles

www.thelancet.com/oncology Vol 16 January 2015 29

objective response (by RECIST version 1.0), clinical benefi t (as defi ned by the sum of complete plus partial responses and stable disease for 24 weeks or more), duration of response, and overall survival. Additional secondary endpoints were safety and tissue and serum biomarker analyses. Finally, we also assessed patient-reported outcomes using the modifi ed Brief Pain Inventory (Short Form; mBPI-sf) done on day 1 of each treatment cycle; the mBPI-sf was used to capture whether palbociclib adds to the commonly reported adverse event seen with aromatase inhibitors (myalgias and joint pain).

Statistical analysisWe used a two-part study design (ie, two sequential cohorts) to allow us to assess both the activity of the palbociclib plus letrozole combination and to determine whether further patient selection on the basis of additional biomarkers (CCND1 or p16) was warranted. We planned to enrol 60 patients (30 per treatment group) into cohort 1 to provide initial safety and effi cacy (progression-free survival) data in patients with oestrogen receptor-positive, HER2-negative, advanced breast cancer. In cohort 2, we planned to include 150 patients (75 per treatment group) who also had CCND1 gene amplifi cation or loss of p16. Cohort 1 was intended to be an exploratory analysis, and the analysis of the primary endpoint was initially intended to be based on cohort 2 only. Assuming 114 progression-free survival events in cohort 2 and using a one-sided α of 0·10, a sample size of 150 would have 80% power to detect an HR of 0·67 (palbociclib plus letrozole vs letrozole alone), including one futility interim analysis. This HR would represent a median progression-free survival of 9 months in the control group and 13·5 months in the experimental group.13

However, an unplanned interim analysis of cohort 1 based on 31 progression-free survival events was done when we noted that almost twice as many patients in the control group were coming off the study because of disease progression. This interim analysis showed clinically meaningful activity of the palbociclib plus letrozole combination compared with letrozole alone (HR 0·35, 95% CI 0·170·72, p=0·006). These preliminary results from cohort 1 also suggested that further patient selection based on CCND1 amplifi cation or p16 loss was unlikely to further improve patient outcome over the use of oestrogen receptor and HER2 status alone (HR with CCND1 or p16 copy changes 0·37 [95% CI 0·10–1·40; p=0·13] vs HR with no CCND1 or p16 copy changes 0·19 [0·05–0·67; p=0·0045]). As a result, we stopped further enrolment into cohort 2 and amended the statistical analysis plan such that the primary endpoint would be analysed in cohorts 1 and 2 combined instead of cohort 2 alone. These study changes were made prospectively without any effi cacy results from cohort 2 and were

Figure 2: Progression-free survival (intention-to-treat population)HR=hazard ratio.

0

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Palbociclib plus letrozoleLetrozole

HR 0·488 (95% CI 0·319–0·748; one-sided p=0·0004)

HR 0·299 (95% CI 0·156–0·572; one-sided p<0·0001)

HR 0·508 (95% CI 0·303–0·853; one-sided p=0·0046)


Letrozole1510

102

2920

2114

5049

54133

3726

FINN Lan Oncol 2015

Median PFS LET 10.2 m (95%CI 5.7-12.6)

LET-PALBO 20.2 m (95%CI 13.8-27.5)

Median PFS LET 5.7 m (95%CI 2.6-10.5) LET-PALBO 26.1 m (95%CI 11.2-NE)

Median PFS LET 11.1 m (95%7.1-16.4) LET-PALBO 18.1 m (95%CI 13.1-27.5)

PALOMA 3 : diseño del estudio : 2ª Línea: hormonoresistentes

Placebo(3wkson/1wkoff)

+Fulvestrant†

(500mgIMq4w)

Palbociclib(125mgQD;

3wkson/1wkoff)+

Fulvestrant†(500mgIMq4w)

†administeredonDays1and15ofCycle1.

●  Visceralmetastases

●  Sensi-vitytopriorhormonaltherapy

●  Pre-/peri-vsPost-menopausal

2:1 Randomization

N=521

Stra8fica8on:

•  Post-menopausalpaCentsmusthaveprogressedonprioraromataseinhibitortherapy.

n=347

n=174

•  HR+,HER2–ABC•  Pre-/peri-*orpost-menopausal•  Progressedonpriorendocrinetherapy:–  Onorwithin12moadjuvant–  OntherapyforABC

•  ≤1priorchemotherapyregimenforadvancedcancer

*Allreceivedgoserelin.

BACKGROUND�O Standard of care for hormone receptor (HR)–positive breast cancer currently includes selective estrogen receptor modulators and aromatase inhibitors; despite these treatment options, many patients fail to benefit from endocrine therapy and develop resistant disease.1,2

�O Overexpression of cyclin-dependent kinases 4 and 6 (CDK 4/6) has been demonstrated to play a role in the development of HR-positive breast cancer by promoting G1- to S-phase transition, leading to increased proliferation.3

�O Palbociclib (IBRANCE®; PD-0332991) is a first-in-class, orally bioavailable selective inhibitor of CDK 4/6 that prevents DNA synthesis by inhibiting G1- to S-phase progression.4,5

�O PALOMA-3 was a randomized, double-blind, placebo-controlled, phase 3 trial of palbociclib combined with fulvestrant versus placebo and fulvestrant in women with HR-positive/human epidermal growth factor receptor 2 (HER2)−negative metastatic breast cancer (MBC) whose disease had progressed after prior endocrine therapy.3

– PALOMA-3 was stopped early based on the recommendation from an independent data monitoring committee at the interim analysis; palbociclib plus fulvestrant was associated with a median progression-free survival (PFS) of 9.2 months compared with 3.8 months for placebo plus fulvestrant (hazard ratio [HR]=0.42 [95% CI, 0.32–0.56] P<0.001).3

�O We report here mature safety and efficacy data from PALOMA-3 with longer follow-up, focusing on varying degrees of endocrine resistance

METHODSStudy Population�O Key Inclusion Criteria3

– Pre- and postmenopausal women (≥18 years of age) with HR-positive, HER2-negative MBC whose disease progressed on prior endocrine therapy (ie, aromatase inhibitors for postmenopausal women and tamoxifen for premenopausal women)

�O Key Exclusion Criteria

– Prior treatment with any CDK inhibitor, fulvestrant, everolimus, or any phosphoinositide 3-kinase or mechanistic target of rapamycin (mTOR) pathway inhibitor

– Active brain metastases and symptomatic visceral spread that could lead to life-threatening complications

Study Design �O The PALOMA-3 (NCT01942135) study design is shown in Figure 1.3

�O Treatment continued until disease progression, unacceptable toxicity, or study withdrawal.3

Figure 1. PALOMA-3 Study Design

StratificationƔ Visceral metastasesƔ Sensitivity to prior hormonal therapyƔ Premenopausal/ perimenopausal vs postmenopausal

n=347

n=174

2:1 RandomizationN=521c

Ɣ HR-positive, HER2-negative MBCƔ Premenopausal/perimenopausala,b or postmenopausalbƔ Progressed on prior endocrine therapy� í�2Q�RU�ZLWKLQ��PR�DGMXYDQW� í�2Q�WKHUDS\�IRU�0%&Ɣ ��SULRU�FKHPRWKHUDS\�UHJLPHQ� IRU�DGYDQFHG�FDQFHU

Palbociclib(125 mg QD;

��ZN�RQ��ZN�RII�+

Fulvestrantd��PJ�,0�4�:�

Placebo��ZN�RQ��ZN�RII�

+Fulvestrantd

��PJ�,0�4�:�

aAll received goserelin.bMust have progressed on prior tamoxifen (premenopausal/perimenopausal) or aromatase inhibitor therapy (postmenopausal).cPatients randomized.dAdministered on d 1 and 15 of cycle 1, then every 28 d.HR=hormone receptor; HER2=human epidermal growth factor receptor 2; IM=intramuscular; MBC=metastatic breast cancer; QD=once daily; Q4W=every 4 weeks.

Study Endpoints�O Primary endpoint: investigator-assessed PFS according to Response Evaluation Criteria in Solid Tumors, version 1.13

�O Secondary endpoints included overall response rate (ORR; clinical response is reported as a radiologically confirmed response), clinical benefit rate (CBR; complete response or partial response or stable disease for ≥24 weeks), overall survival, patient-reported outcomes, and safety.3

�O Tumor assessments were performed every 8 weeks; after 1 year, they were performed every 12 weeks in patients with a bone lesion only at baseline.3

�O Adverse events (AEs) were graded and reported using National Cancer Institute Common Terminology Criteria, version 4.0.

Statistical Analyses�O Statistical analysis cutoff date was March 16, 2015 (259 PFS events).�O Efficacy analyses were based on the intent-to-treat (ITT) principle.

– PFS was summarized with the Kaplan-Meier method; Cox proportional hazards model was used to estimate HR. – Rates of binary endpoints were determined using the odds ratio estimator and stratified exact test.

RESULTSPatients and Treatment�O Of the 521 patients randomized in the PALOMA-3 trial, 345 received palbociclib plus fulvestrant (palbociclib group) and 172 received placebo plus fulvestrant (control group).

�O Key baseline clinical characteristics were well balanced between the 2 treatment arms.

Efficacy�O As of March 2015, a total of 259 PFS events occurred (145 events [42%] in the palbociclib group and 114 [66%] in the control group). The median follow-up was 8.9 months (range, 8.7–9.2) for the palbociclib and control groups, with 191 patients (55%) in the palbociclib group vs 51 patients (29%) in the control group remaining on treatment.

�O Median PFS for the palbociclib group was 9.5 (95% CI, 9.2–11.0) and 4.6 months (95% CI, 3.5–5.6) for the control group, HR=0.46 (95% CI, 0.36–0.59); P<0.0001 (Figure 2).

– The PFS benefit of palbociclib was confirmed in a blinded independent central review of a random sample of patients (Figure 3).

Figure 2. Progression-Free Survival* – Intent-to-Treat PopulationP

rog

ress

ion

-Fre

eS

urv

iva

l P

rob

ab

ilit

y, %

Time, mo

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

20

40

60

80

100

Hazard Ratio=0.4695% CI (0.36 – 0.59)P<0.0001

Number of Patients at Risk:PAL+FULPCB+FUL

347174

333165

281112

273105

24783

24480

20259

19758

9122

8522

3213

237

72

71

10

0

Palbociclib+Fulvestrant (n=347)Median PFS=9.5 months95% CI (9.2–11.0)

Placebo+Fulvestrant (n=174)Median PFS=4.6 months95% CI (3.5–5.6)

FUL=fulvestrant; PAL=palbociclib; PCB=placebo; PFS=progression-free survival. *Investigator-assessed.

Figure 3. Progression-Free Survival In a Random Sample of Patients Assessed By Blinded Central Review (n=211)

Pro

gre

ssio

n-F

ree

Su

rviv

al

Pro

ba

bilit

y, %

Time, mo

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

20

40

60

80

100

Hazard Ratio=0.3795% CI (0.23 – 0.59)P<0.0001


14764

14361

11937

11636

10324

10024

7818

7718

335

335

133

93

41

41

10

0

Palbociclib+Fulvestrant (n=147)Median PFS=NE


FUL=fulvestrant; NE=not estimable; PAL=palbociclib; PCB=placebo; PFS=progression-free survival.

Presented at the 38th San Antonio Breast Cancer Symposium (SABCS); December 8–12, 2015; San Antonio, Texas, USA

PALOMA-3: Phase 3 Trial of Fulvestrant With or Without Palbociclib in Pre- and Postmenopausal Women With Hormone Receptor−Positive, HER2-Negative Metastatic Breast Cancer That Progressed on Prior Endocrine Therapy—Confirmed Safety and Efficacy in Endocrine-Sensitive and Refractory Disease Massimo Cristofanilli,1 Igor Bondarenko,2 Jungsil Ro,3 Seock-Ah Im,4 Norikazu Masuda,5 Marco Colleoni,6 Angela M. DeMichele,7 Sherene Loi,8 Sunil Verma,9 Hiroji Iwata,10 Cynthia Huang Bartlett,11 Ke Zhang,12 Kathy Puyana Theall,13 Nicholas Turner,14 Dennis Slamon15

1Northwestern University, Chicago, IL, USA; 2Dnipropetrovsk Medical Academy, City Multiple-Discipline Clinical Hospital #4, Dnipropetrovsk, Ukraine; 3National Cancer Center, Goyang-si, Korea; 4Seoul National University Hospital, Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Korea; 5Osaka National Hospital, Osaka, Japan; 6Istituto Europeo di Oncologia, Milan, Italy; 7University of Pennsylvania, Philadelphia, PA, USA; 8Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; 9Sunnybrook Odette Cancer Centre, Toronto, ON, Canada; 10Aichi Cancer Center Hospital, Nagoya, Japan 11Pfizer Inc, Collegeville, PA, USA; 12Pfizer Inc, La Jolla, CA, USA; 13Pfizer Inc, Cambridge, MA, USA; 14Royal Marsden Hospital and Institute of Cancer Research, London, UK; 15University of California Los Angeles, Los Angeles, CA, USA

P4-13-01

�O ORR was observed in 19.0% (95% CI, 15.0–23.6) of patients in the palbociclib group compared with 8.6% (95% CI, 4.9–13.8) in the control group in the ITT population, OR=2.47 (95% CI, 1.36–4.91; P=0.0019). In patients with measurable disease at baseline, ORR was observed in 24.6% (95% CI, 19.6–30.2) vs 10.9% (95% CI, 6.2–17.3), OR=2.69 (95% CI, 1.43–5.26; P=0.0012 (Figure 4).

Figure 4. Confirmed Overall Tumor Response and Clinical Benefit Rate, Investigator Assessed

ORR CBR*Intent-to-treat Intent-to-treatMeasurable

diseaseMeasurable

disease

Population: Intent-to-treat Measurable disease Intent-to-treat Measurable disease

Odds ratio (95% CI)† 2.47 (1.36–4.91) 2.69 (1.43–5.26) 3.05 (2.07–4.61) 3.10 (1.99–4.92)

P<0.0001‡

P=0.0012‡

P=0.0019‡

P<0.0001‡

Pa

tie

nts

, %

Palbociclib+Fulvestrant Placebo+FulvestrantPR CR SDPR CR SD

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

CBR=clinical benefit response; CI=confidence interval; CR=complete response; ORR=objective response rate; PR=partial response; SD=stable disease ≥24 wk.*Clinical benefit response rate=complete response or partial response or stable disease ≥24 wk.†CI was calculated using the exact (Clopper-Pearson) method. ‡Two-sided exact test stratified by the presence of visceral metastases and sensitivity to prior hormonal therapy per randomization.

�O Clinical benefit was observed in 66.6% (95% CI, 61.3–71.5) of patients in the palbociclib group vs 39.7% (95% CI, 32.3–47.3) of patients in the control group, OR=3.05 (95% CI, 2.07–4.61); P<0.0001.

�O PFS benefit of palbociclib plus fulvestrant vs placebo plus fulvestrant was compared in patients across various subgroups.

– Patients with pre-/perimenopausal and postmenopausal status

• Median PFS in pre-/perimenopausal patients of 9.5 months (95% CI, 7.4 to not estimable) vs 5.6 months (95% CI, 1.8–7.6), HR=0.50 (95% CI, 0.29–0.87); P=0.0065

• Median PFS in postmenopausal women of 9.9 months (95% CI, 8.5–11.0) vs 3.9 months (95% CI, 3.5–5.5), HR=0.45 (95% CI, 0.34–0.59); P<0.0001

– Patients with no prior systemic therapy in the metastatic setting (Figure 5)

• Median PFS of 9.5 months (95% CI, 7.4 to not estimable) vs 5.4 months (95% CI, 2.1–10.9), HR=0.55 (95% CI, 0.32–0.92); P=0.0214

– Patients whose disease was responsive to prior endocrine therapy (Figure 6)

• Median PFS of 10.2 months (95% CI, 9.4–11.2) vs 4.2 months (95% CI, 3.5–5.6), HR=0.42 (95% CI, 0.32–0.56); P<0.0001

– Patients who were exposed to an aromatase inhibitor as their most recent therapy (Figure 7)


Figure 5. Progression-Free Survival* in Patients With No Prior Systemic Therapy in the Metastatic Setting

Pro

gre

ssio

n-F

ree

Su

rviv

al

Pro

ba

bilit

y, %

Time, mo

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

20

40

60

80

100

Hazard Ratio=0.5595% CI (0.32–0.92)P=0.0214


7440

7036

5925

5724

5319

5218

4513

4513

186

186

85

72

10

1 0

Palbociclib+Fulvestrant (n=74)Median PFS=9.5 months95% CI (7.4–NE)


FUL=fulvestrant; NE=not estimable; PAL=palbociclib; PCB=placebo; PFS=progression-free survival. *Investigator-assessed.

Figure 6. Progression-Free Survival* in Patients Whose Disease Was Responsive to Prior Endocrine Therapy

Pro

gre

ssio

n-F

ree

S

urv

iva

l P

rob

ab

ilit

y, %

Time, mo

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

0.2

0.4

0.6

0.8

1.0

Hazard Ratio=0.4295% CI (0.32 – 0.56)P<0.0001


274136

267130

22890

22384

20364

20062

17145

16644

8018

7618

2911

216

72

71

10

0




Figure 7. Progression-Free Survival* in Patients Exposed to an Aromatase Inhibitor as Their Most Recent Therapy

Pro

gre

ssio

n-F

ree

S

urv

iva

l P

rob

ab

ilit

y, %

Time, mo0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

0.2

0.0

0.4

0.6

0.8

1.0 Palbociclib+Fulvestrant (n=237)Median PFS=9.5 months95% CI (9.2–11.0)

Hazard Ratio=0.4295% CI (0.31 – 0.56)P<0.0001

Number of Patients at Risk:


PAL+FULPCB+FUL

237119

230114

19378

18773

17153

16951

14237

13836

6015

5515

229

165

42

41

00


Safety�O Hematologic toxicities were the most frequently reported AEs during the study (Table 1). Of the AEs of any grade:

– Neutropenia was reported in 81% of patients receiving palbociclib plus fulvestrant vs 3% of patients receiving placebo plus fulvestrant.

– Febrile neutropenia was reported in 0.9% of patients receiving palbociclib plus fulvestrant vs 0.6% of patients receiving placebo plus fulvestrant.

– Leukopenia was reported in 50% of patients receiving palbociclib plus fulvestrant vs 4% of patients receiving placebo plus fulvestrant.

�O Study discontinuation due to AEs occurred in 4% of patients receiving palbociclib plus fulvestrant vs 2% of patients receiving placebo plus fulvestrant.

Table 1. Frequency of Adverse Events Occurring in *10% in the Palbociclib Plus Fulvestrant Group (All Causalities and All Cycles)

Palbociclib Plus Fulvestrant (n=345) Placebo Plus Fulvestrant (n=172)

Adverse Events*All

GradesGrade

1Grade

2Grade

3Grade

4All

GradesGrade

1Grade

2Grade

3Grade

4Any adverse event 340 (99) 18 (5) 67 (19) 210 (61) 41 (12) 154 (90) 58 (34) 55 (32) 34 (20) 4 (2)HematologicNeutropenia† 279 (81) 6 (2) 50 (14) 189 (55) 34 (10) 6 (3) 2 (1) 3 (2) 0 1 (1)Anemia† 96 (28) 44 (13) 42 (12) 10 (3) 0 19 (11) 8 (5) 8 (5) 3 (2) 0Leukopenia† 171 (50) 14 (4) 62 (18) 93 (27) 2 (1) 7 (4) 4 (2) 1 (1) 1 (1) 1 (1)Thrombocytopenia† 73 (21) 51 (15) 14 (4) 6 (2) 2 (1) 0 0 0 0 0Nonhematologic Infections† 144 (42) 55 (16) 82 (24) 6 (2) 1 (<1) 52 (30) 22 (13) 25 (15) 5 (3) 0Fatigue 135 (39) 81 (23) 46 (13) 8 (2) 0 49 (28) 33 (19) 14 (8) 2 (1) 0Nausea 112 (32) 82 (24) 30 (9) 0 0 47 (27) 42 (24) 4 (2) 1 (1) 0Headache 80 (23) 65 (19) 13 (4) 2 (1) 0 33 (19) 27 (16) 6 (3) 0 0Diarrhea 74 (21) 60 (17) 14 (4) 0 0 32 (19) 25 (15) 6 (3) 1 (1) 0Constipation 66 (19) 55 (16) 11 (3) 0 0 27 (16) 24 (14) 3 (2) 0 0Alopecia 58 (17) 53 (15) 5 (1) 0 0 11 (6) 11 (6) 0 0 0Vomiting 58 (17) 41 (12) 16 (5) 1 (<1) 0 25 (15) 22 (13) 2 (1) 1 (1) 0Hot flush 53 (15) 42 (12) 11 (3) 0 0 29 (17) 23 (13) 5 (3) 1 (1) 0Decreased appetite 52 (15) 37 (11) 12 (3) 3 (1) 0 14 (8) 10 (6) 3 (2) 1 (1) 0Rash† 52 (15) 48 (14) 2 (1) 2 (1) 0 9 (5) 8 (5) 1 (1) 0 0Back pain 51 (15) 31 (9) 16 (5) 4 (1) 0 29 (17) 16 (9) 10 (6) 3 (2) 0Cough 51 (15) 40 (12) 11 (3) 0 0 22 (13) 15 (9) 7 (4) 0 0Arthralgia 49 (14) 37 (11) 11 (3) 1 (<1) 0 27 (16) 22 (13) 5 (3) 0 0Pain in extremity 43 (12) 30 (9) 13 (4) 0 0 21 (12) 11 (6) 7 (4) 3 (2) 0 Stomatitis 43 (12) 28 (8) 13 (4) 2 (1) 0 4 (2) 4 (2) 0 0 0Dizziness 41 (12) 37 (11) 3 (1) 1 (<1) 0 16 (9) 14 (8) 2 (1) 0 0 Dyspnea 40 (12) 21 (6) 18 (5) 0 1 (<1) 14 (8) 8 (5) 4 (2) 2 (1) 0Pyrexia 38 (11) 34 (10) 3 (1) 1 (<1) 0 9 (5) 6 (3) 3 (2) 0 0Insomnia 33 (10) 26 (8) 6 (2) 1 (<1) 0 12 (7) 8 (5) 4 (2) 0 0Data are n (%).*Adverse events graded in accordance with the maximum Common Terminology Criteria for Adverse Events Grade, Version 4.0, and the Medical Dictionary for Regulatory Activities (MedDRA), Version 18.0.†Clustered preferred terms defined as follows: anemia is any event having a preferred term equivalent to anemia or hematocrit decreased or hemoglobin decreased; infections is defined as any event having a preferred term of the System Organ Class infections and infestations; leukopenia is any event having a preferred term equivalent to leukopenia or white blood cell count decreased; neutropenia is any event having a preferred term equivalent to neutropenia or neutrophil count decreased; rash is any event having a preferred term equivalent to dermatitis or dermatitis acneiform or rash or rash erythematous or rash maculo-papular or rash papular or rash pruritic; thrombocytopenia is any event having a preferred term equivalent to platelet count decreased or thrombocytopenia.

CONCLUSIONS�O With a longer follow-up, the mature data showed that palbociclib in combination with

fulvestrant resulted in a statistically significant improvement over fulvestrant alone for the ORR in the ITT population (19.0% vs 8.6%, respectively); in patients with measurable disease (24.6% vs 10.9%, respectively); and for CBR in the ITT population (66.6% vs 39.7%, respectively).

�O Palbociclib plus fulvestrant administration significantly improved PFS compared with placebo plus fulvestrant (9.5 vs 4.6 months; HR=0.46; P<0.0001) and resulted in consistent benefit across all subgroups analyzed, including both pre- and postmenopausal patients.

�O No new safety concerns were identified for palbociclib plus fulvestrant during the extended follow-up period (8.9 months); the safety profile remained favorable.

�O Neutropenia was the most common AE in the palbociclib group; however, the rate of febrile neutropenia was low and similar to that observed in patients treated with fulvestrant alone.

�O Palbociclib in combination with fulvestrant may be an ideal choice in patients with HR-positive MBC whose disease has progressed on endocrine therapy.

REFERENCES1. Lumachi F, et al. World J Biol Chem. 2015;6(3):231-239.2. Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.3. Turner NC, et al. N Engl J Med. 2015;373(3):209-219.4. Fry DW, et al. Mol Cancer Ther. 2004;3(11):1427-1438.5. Toogood PL, et al. J Med Chem. 2005;48(7):2388-2406.

ACKNOWLEDGMENTSThis study was funded by Pfizer Inc. Medical writing support was provided by Susan Reinwald, PhD, and Kevin O’Regan, PhD (Complete Healthcare Communications, LLC) and was funded by Pfizer Inc.

This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.

Copyright (C) 2015. All rights reserved

CristofanilliM.SABCS2015

BACKGROUND�O Standard of care for hormone receptor (HR)–positive breast cancer currently includes selective estrogen receptor modulators and aromatase inhibitors; despite these treatment options, many patients fail to benefit from endocrine therapy and develop resistant disease.1,2

�O Overexpression of cyclin-dependent kinases 4 and 6 (CDK 4/6) has been demonstrated to play a role in the development of HR-positive breast cancer by promoting G1- to S-phase transition, leading to increased proliferation.3

�O Palbociclib (IBRANCE®; PD-0332991) is a first-in-class, orally bioavailable selective inhibitor of CDK 4/6 that prevents DNA synthesis by inhibiting G1- to S-phase progression.4,5

�O PALOMA-3 was a randomized, double-blind, placebo-controlled, phase 3 trial of palbociclib combined with fulvestrant versus placebo and fulvestrant in women with HR-positive/human epidermal growth factor receptor 2 (HER2)−negative metastatic breast cancer (MBC) whose disease had progressed after prior endocrine therapy.3

– PALOMA-3 was stopped early based on the recommendation from an independent data monitoring committee at the interim analysis; palbociclib plus fulvestrant was associated with a median progression-free survival (PFS) of 9.2 months compared with 3.8 months for placebo plus fulvestrant (hazard ratio [HR]=0.42 [95% CI, 0.32–0.56] P<0.001).3

�O We report here mature safety and efficacy data from PALOMA-3 with longer follow-up, focusing on varying degrees of endocrine resistance

METHODSStudy Population�O Key Inclusion Criteria3

– Pre- and postmenopausal women (≥18 years of age) with HR-positive, HER2-negative MBC whose disease progressed on prior endocrine therapy (ie, aromatase inhibitors for postmenopausal women and tamoxifen for premenopausal women)

�O Key Exclusion Criteria

– Prior treatment with any CDK inhibitor, fulvestrant, everolimus, or any phosphoinositide 3-kinase or mechanistic target of rapamycin (mTOR) pathway inhibitor

– Active brain metastases and symptomatic visceral spread that could lead to life-threatening complications

Study Design �O The PALOMA-3 (NCT01942135) study design is shown in Figure 1.3

�O Treatment continued until disease progression, unacceptable toxicity, or study withdrawal.3

Figure 1. PALOMA-3 Study Design

StratificationƔ Visceral metastasesƔ Sensitivity to prior hormonal therapyƔ Premenopausal/ perimenopausal vs postmenopausal

n=347

n=174

2:1 RandomizationN=521c

Ɣ HR-positive, HER2-negative MBCƔ Premenopausal/perimenopausala,b or postmenopausalbƔ Progressed on prior endocrine therapy� í�2Q�RU�ZLWKLQ��PR�DGMXYDQW� í�2Q�WKHUDS\�IRU�0%&Ɣ ��SULRU�FKHPRWKHUDS\�UHJLPHQ� IRU�DGYDQFHG�FDQFHU

Palbociclib(125 mg QD;

��ZN�RQ��ZN�RII�+

Fulvestrantd��PJ�,0�4�:�

Placebo��ZN�RQ��ZN�RII�

+Fulvestrantd

��PJ�,0�4�:�

aAll received goserelin.bMust have progressed on prior tamoxifen (premenopausal/perimenopausal) or aromatase inhibitor therapy (postmenopausal).cPatients randomized.dAdministered on d 1 and 15 of cycle 1, then every 28 d.HR=hormone receptor; HER2=human epidermal growth factor receptor 2; IM=intramuscular; MBC=metastatic breast cancer; QD=once daily; Q4W=every 4 weeks.

Study Endpoints�O Primary endpoint: investigator-assessed PFS according to Response Evaluation Criteria in Solid Tumors, version 1.13

�O Secondary endpoints included overall response rate (ORR; clinical response is reported as a radiologically confirmed response), clinical benefit rate (CBR; complete response or partial response or stable disease for ≥24 weeks), overall survival, patient-reported outcomes, and safety.3

�O Tumor assessments were performed every 8 weeks; after 1 year, they were performed every 12 weeks in patients with a bone lesion only at baseline.3

�O Adverse events (AEs) were graded and reported using National Cancer Institute Common Terminology Criteria, version 4.0.

Statistical Analyses�O Statistical analysis cutoff date was March 16, 2015 (259 PFS events).�O Efficacy analyses were based on the intent-to-treat (ITT) principle.

– PFS was summarized with the Kaplan-Meier method; Cox proportional hazards model was used to estimate HR. – Rates of binary endpoints were determined using the odds ratio estimator and stratified exact test.

RESULTSPatients and Treatment�O Of the 521 patients randomized in the PALOMA-3 trial, 345 received palbociclib plus fulvestrant (palbociclib group) and 172 received placebo plus fulvestrant (control group).

�O Key baseline clinical characteristics were well balanced between the 2 treatment arms.

Efficacy�O As of March 2015, a total of 259 PFS events occurred (145 events [42%] in the palbociclib group and 114 [66%] in the control group). The median follow-up was 8.9 months (range, 8.7–9.2) for the palbociclib and control groups, with 191 patients (55%) in the palbociclib group vs 51 patients (29%) in the control group remaining on treatment.

�O Median PFS for the palbociclib group was 9.5 (95% CI, 9.2–11.0) and 4.6 months (95% CI, 3.5–5.6) for the control group, HR=0.46 (95% CI, 0.36–0.59); P<0.0001 (Figure 2).

– The PFS benefit of palbociclib was confirmed in a blinded independent central review of a random sample of patients (Figure 3).

Figure 2. Progression-Free Survival* – Intent-to-Treat Population

Prog

ress

ion-

Free

Surv

ival

Pro

babi

lity,

%

Time, mo

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

20

40

60

80

100

Hazard Ratio=0.4695% CI (0.36 – 0.59)P<0.0001


347174

333165

281112

273105

24783

24480

20259

19758

9122

8522

3213

237

72

71

10

0




Figure 3. Progression-Free Survival In a Random Sample of Patients Assessed By Blinded Central Review (n=211)

Prog

ress

ion-

Free

Surv

ival

Pro

babi

lity,

%

Time, mo

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

20

40

60

80

100

Hazard Ratio=0.3795% CI (0.23 – 0.59)P<0.0001


14764

14361

11937

11636

10324

10024

7818

7718

335

335

133

93

41

41

10

0

Palbociclib+Fulvestrant (n=147)Median PFS=NE


FUL=fulvestrant; NE=not estimable; PAL=palbociclib; PCB=placebo; PFS=progression-free survival.

Presented at the 38th San Antonio Breast Cancer Symposium (SABCS); December 8–12, 2015; San Antonio, Texas, USA

PALOMA-3: Phase 3 Trial of Fulvestrant With or Without Palbociclib in Pre- and Postmenopausal Women With Hormone Receptor−Positive, HER2-Negative Metastatic Breast Cancer That Progressed on Prior Endocrine Therapy—Confirmed Safety and Efficacy in Endocrine-Sensitive and Refractory Disease Massimo Cristofanilli,1 Igor Bondarenko,2 Jungsil Ro,3 Seock-Ah Im,4 Norikazu Masuda,5 Marco Colleoni,6 Angela M. DeMichele,7 Sherene Loi,8 Sunil Verma,9 Hiroji Iwata,10 Cynthia Huang Bartlett,11 Ke Zhang,12 Kathy Puyana Theall,13 Nicholas Turner,14 Dennis Slamon15

1Northwestern University, Chicago, IL, USA; 2Dnipropetrovsk Medical Academy, City Multiple-Discipline Clinical Hospital #4, Dnipropetrovsk, Ukraine; 3National Cancer Center, Goyang-si, Korea; 4Seoul National University Hospital, Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Korea; 5Osaka National Hospital, Osaka, Japan; 6Istituto Europeo di Oncologia, Milan, Italy; 7University of Pennsylvania, Philadelphia, PA, USA; 8Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; 9Sunnybrook Odette Cancer Centre, Toronto, ON, Canada; 10Aichi Cancer Center Hospital, Nagoya, Japan 11Pfizer Inc, Collegeville, PA, USA; 12Pfizer Inc, La Jolla, CA, USA; 13Pfizer Inc, Cambridge, MA, USA; 14Royal Marsden Hospital and Institute of Cancer Research, London, UK; 15University of California Los Angeles, Los Angeles, CA, USA

P4-13-01

�O ORR was observed in 19.0% (95% CI, 15.0–23.6) of patients in the palbociclib group compared with 8.6% (95% CI, 4.9–13.8) in the control group in the ITT population, OR=2.47 (95% CI, 1.36–4.91; P=0.0019). In patients with measurable disease at baseline, ORR was observed in 24.6% (95% CI, 19.6–30.2) vs 10.9% (95% CI, 6.2–17.3), OR=2.69 (95% CI, 1.43–5.26; P=0.0012 (Figure 4).

Figure 4. Confirmed Overall Tumor Response and Clinical Benefit Rate, Investigator Assessed

ORR CBR*Intent-to-treat Intent-to-treatMeasurable

diseaseMeasurable

disease

Population: Intent-to-treat Measurable disease Intent-to-treat Measurable disease

Odds ratio (95% CI)† 2.47 (1.36–4.91) 2.69 (1.43–5.26) 3.05 (2.07–4.61) 3.10 (1.99–4.92)

P<0.0001‡

P=0.0012‡

P=0.0019‡

P<0.0001‡

Pati

ents

, %

Palbociclib+Fulvestrant Placebo+FulvestrantPR CR SDPR CR SD

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

CBR=clinical benefit response; CI=confidence interval; CR=complete response; ORR=objective response rate; PR=partial response; SD=stable disease ≥24 wk.*Clinical benefit response rate=complete response or partial response or stable disease ≥24 wk.†CI was calculated using the exact (Clopper-Pearson) method. ‡Two-sided exact test stratified by the presence of visceral metastases and sensitivity to prior hormonal therapy per randomization.

�O Clinical benefit was observed in 66.6% (95% CI, 61.3–71.5) of patients in the palbociclib group vs 39.7% (95% CI, 32.3–47.3) of patients in the control group, OR=3.05 (95% CI, 2.07–4.61); P<0.0001.

�O PFS benefit of palbociclib plus fulvestrant vs placebo plus fulvestrant was compared in patients across various subgroups.

– Patients with pre-/perimenopausal and postmenopausal status

• Median PFS in pre-/perimenopausal patients of 9.5 months (95% CI, 7.4 to not estimable) vs 5.6 months (95% CI, 1.8–7.6), HR=0.50 (95% CI, 0.29–0.87); P=0.0065

• Median PFS in postmenopausal women of 9.9 months (95% CI, 8.5–11.0) vs 3.9 months (95% CI, 3.5–5.5), HR=0.45 (95% CI, 0.34–0.59); P<0.0001

– Patients with no prior systemic therapy in the metastatic setting (Figure 5)

• Median PFS of 9.5 months (95% CI, 7.4 to not estimable) vs 5.4 months (95% CI, 2.1–10.9), HR=0.55 (95% CI, 0.32–0.92); P=0.0214

– Patients whose disease was responsive to prior endocrine therapy (Figure 6)


– Patients who were exposed to an aromatase inhibitor as their most recent therapy (Figure 7)


Figure 5. Progression-Free Survival* in Patients With No Prior Systemic Therapy in the Metastatic Setting

Prog

ress

ion-

Free

Surv

ival

Pro

babi

lity,

%

Time, mo

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

20

40

60

80

100

Hazard Ratio=0.5595% CI (0.32–0.92)P=0.0214


7440

7036

5925

5724

5319

5218

4513

4513

186

186

85

72

10

1 0

Palbociclib+Fulvestrant (n=74)Median PFS=9.5 months95% CI (7.4–NE)


FUL=fulvestrant; NE=not estimable; PAL=palbociclib; PCB=placebo; PFS=progression-free survival. *Investigator-assessed.

Figure 6. Progression-Free Survival* in Patients Whose Disease Was Responsive to Prior Endocrine Therapy

Prog

ress

ion-

Free

Su

rviv

al P

roba

bilit

y, %

Time, mo

0.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

0.2

0.4

0.6

0.8

1.0

Hazard Ratio=0.4295% CI (0.32 – 0.56)P<0.0001


274136

267130

22890

22384

20364

20062

17145

16644

8018

7618

2911

216

72

71

10

0




Figure 7. Progression-Free Survival* in Patients Exposed to an Aromatase Inhibitor as Their Most Recent Therapy

Prog

ress

ion-

Free

Su

rviv

al P

roba

bilit

y, %

Time, mo0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

0.2

0.0

0.4

0.6

0.8

1.0 Palbociclib+Fulvestrant (n=237)Median PFS=9.5 months95% CI (9.2–11.0)

Hazard Ratio=0.4295% CI (0.31 – 0.56)P<0.0001

Number of Patients at Risk:


PAL+FULPCB+FUL

237119

230114

19378

18773

17153

16951

14237

13836

6015

5515

229

165

42

41

00


Safety�O Hematologic toxicities were the most frequently reported AEs during the study (Table 1). Of the AEs of any grade:

– Neutropenia was reported in 81% of patients receiving palbociclib plus fulvestrant vs 3% of patients receiving placebo plus fulvestrant.

– Febrile neutropenia was reported in 0.9% of patients receiving palbociclib plus fulvestrant vs 0.6% of patients receiving placebo plus fulvestrant.

– Leukopenia was reported in 50% of patients receiving palbociclib plus fulvestrant vs 4% of patients receiving placebo plus fulvestrant.

�O Study discontinuation due to AEs occurred in 4% of patients receiving palbociclib plus fulvestrant vs 2% of patients receiving placebo plus fulvestrant.

Table 1. Frequency of Adverse Events Occurring in *10% in the Palbociclib Plus Fulvestrant Group (All Causalities and All Cycles)

Palbociclib Plus Fulvestrant (n=345) Placebo Plus Fulvestrant (n=172)

Adverse Events*All

GradesGrade

1Grade

2Grade

3Grade

4All

GradesGrade

1Grade

2Grade

3Grade

4Any adverse event 340 (99) 18 (5) 67 (19) 210 (61) 41 (12) 154 (90) 58 (34) 55 (32) 34 (20) 4 (2)HematologicNeutropenia† 279 (81) 6 (2) 50 (14) 189 (55) 34 (10) 6 (3) 2 (1) 3 (2) 0 1 (1)Anemia† 96 (28) 44 (13) 42 (12) 10 (3) 0 19 (11) 8 (5) 8 (5) 3 (2) 0Leukopenia† 171 (50) 14 (4) 62 (18) 93 (27) 2 (1) 7 (4) 4 (2) 1 (1) 1 (1) 1 (1)Thrombocytopenia† 73 (21) 51 (15) 14 (4) 6 (2) 2 (1) 0 0 0 0 0Nonhematologic Infections† 144 (42) 55 (16) 82 (24) 6 (2) 1 (<1) 52 (30) 22 (13) 25 (15) 5 (3) 0Fatigue 135 (39) 81 (23) 46 (13) 8 (2) 0 49 (28) 33 (19) 14 (8) 2 (1) 0Nausea 112 (32) 82 (24) 30 (9) 0 0 47 (27) 42 (24) 4 (2) 1 (1) 0Headache 80 (23) 65 (19) 13 (4) 2 (1) 0 33 (19) 27 (16) 6 (3) 0 0Diarrhea 74 (21) 60 (17) 14 (4) 0 0 32 (19) 25 (15) 6 (3) 1 (1) 0Constipation 66 (19) 55 (16) 11 (3) 0 0 27 (16) 24 (14) 3 (2) 0 0Alopecia 58 (17) 53 (15) 5 (1) 0 0 11 (6) 11 (6) 0 0 0Vomiting 58 (17) 41 (12) 16 (5) 1 (<1) 0 25 (15) 22 (13) 2 (1) 1 (1) 0Hot flush 53 (15) 42 (12) 11 (3) 0 0 29 (17) 23 (13) 5 (3) 1 (1) 0Decreased appetite 52 (15) 37 (11) 12 (3) 3 (1) 0 14 (8) 10 (6) 3 (2) 1 (1) 0Rash† 52 (15) 48 (14) 2 (1) 2 (1) 0 9 (5) 8 (5) 1 (1) 0 0Back pain 51 (15) 31 (9) 16 (5) 4 (1) 0 29 (17) 16 (9) 10 (6) 3 (2) 0Cough 51 (15) 40 (12) 11 (3) 0 0 22 (13) 15 (9) 7 (4) 0 0Arthralgia 49 (14) 37 (11) 11 (3) 1 (<1) 0 27 (16) 22 (13) 5 (3) 0 0Pain in extremity 43 (12) 30 (9) 13 (4) 0 0 21 (12) 11 (6) 7 (4) 3 (2) 0 Stomatitis 43 (12) 28 (8) 13 (4) 2 (1) 0 4 (2) 4 (2) 0 0 0Dizziness 41 (12) 37 (11) 3 (1) 1 (<1) 0 16 (9) 14 (8) 2 (1) 0 0 Dyspnea 40 (12) 21 (6) 18 (5) 0 1 (<1) 14 (8) 8 (5) 4 (2) 2 (1) 0Pyrexia 38 (11) 34 (10) 3 (1) 1 (<1) 0 9 (5) 6 (3) 3 (2) 0 0Insomnia 33 (10) 26 (8) 6 (2) 1 (<1) 0 12 (7) 8 (5) 4 (2) 0 0Data are n (%).*Adverse events graded in accordance with the maximum Common Terminology Criteria for Adverse Events Grade, Version 4.0, and the Medical Dictionary for Regulatory Activities (MedDRA), Version 18.0.†Clustered preferred terms defined as follows: anemia is any event having a preferred term equivalent to anemia or hematocrit decreased or hemoglobin decreased; infections is defined as any event having a preferred term of the System Organ Class infections and infestations; leukopenia is any event having a preferred term equivalent to leukopenia or white blood cell count decreased; neutropenia is any event having a preferred term equivalent to neutropenia or neutrophil count decreased; rash is any event having a preferred term equivalent to dermatitis or dermatitis acneiform or rash or rash erythematous or rash maculo-papular or rash papular or rash pruritic; thrombocytopenia is any event having a preferred term equivalent to platelet count decreased or thrombocytopenia.

CONCLUSIONS�O With a longer follow-up, the mature data showed that palbociclib in combination with

fulvestrant resulted in a statistically significant improvement over fulvestrant alone for the ORR in the ITT population (19.0% vs 8.6%, respectively); in patients with measurable disease (24.6% vs 10.9%, respectively); and for CBR in the ITT population (66.6% vs 39.7%, respectively).

�O Palbociclib plus fulvestrant administration significantly improved PFS compared with placebo plus fulvestrant (9.5 vs 4.6 months; HR=0.46; P<0.0001) and resulted in consistent benefit across all subgroups analyzed, including both pre- and postmenopausal patients.

�O No new safety concerns were identified for palbociclib plus fulvestrant during the extended follow-up period (8.9 months); the safety profile remained favorable.

�O Neutropenia was the most common AE in the palbociclib group; however, the rate of febrile neutropenia was low and similar to that observed in patients treated with fulvestrant alone.

�O Palbociclib in combination with fulvestrant may be an ideal choice in patients with HR-positive MBC whose disease has progressed on endocrine therapy.

REFERENCES1. Lumachi F, et al. World J Biol Chem. 2015;6(3):231-239.2. Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.3. Turner NC, et al. N Engl J Med. 2015;373(3):209-219.4. Fry DW, et al. Mol Cancer Ther. 2004;3(11):1427-1438.5. Toogood PL, et al. J Med Chem. 2005;48(7):2388-2406.

ACKNOWLEDGMENTSThis study was funded by Pfizer Inc. Medical writing support was provided by Susan Reinwald, PhD, and Kevin O’Regan, PhD (Complete Healthcare Communications, LLC) and was funded by Pfizer Inc.

This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.

Copyright (C) 2015. All rights reserved

ESTUDIO PALOMA-3 •  2ª Línea Hormonoresistentes. •  Pre/ postmenopausicas. PFS: 9,5 m vs 4,6 m HR: 0,46


Ø  1ª Línea IA ( A, si no recibieron tto adyuvante previo con IA). Ø  1ª Línea con Fulvestrant 500 mg ( B, si recibieron tto con IA adyuvante). Ø  1ª Línea Letrozol + Palbociclib es superior en PFS en un estudio fase II, pte el

fase III ( B) *

Ø  2ª Línea tras progresión a IA: Fulvestrant 500 mg o Exemestano+ Everolimus son las mejores opciones ( A).

Ø  2ª Línea tras progresión a IA: Fulvestrant 500 mg + Palbociclib es superior a Fulvestrant (A) *

Ø  Sucesivas líneas poca información de estudios prospectivos : tamoxifeno, IA, Fulvestrant, everolimus-exemestano. Casos seleccionados : progestágenos (C).

Ø  No hay evidencia del uso concomitante de Tto hormonal + QT y por tanto no se recomienda (D)

Ø  Tto hormonal como mantenimiento tras QT, estudios fase II y Observacionales, puede haber beneficio en PFS con el tto hormonal (C).

Ø  QT tto estándar tras fracaso a terapia endocrina, enfermedad agresiva de inicio o resistencia endocrina ( A).


Cuestiones pendientes: Ø Fármacos dirigidos + tto hormonal de entrada ? O una vez refractarios a tto hormonal? Ø Fármacos para prevenir o para revertir la resistencia hormonal? Ø Si es así, como las seleccionamos en ausencia de biomarcadores predictivos? Ø  Papel de nuevos – CDKs en estudio RIBOCICLIB ( Monaleesa) y ABEMACICLIB ( Monarch) y de inhibidores PI3K más selectivos y menos tóxicos- ALPELISIB.

Ø  Y tras progresión a – CDKs y / o PI3Ks?

Ø  Se trabaja en la triple terapia: HORMONA+ INH CKK + IN MTOR.

Ø  En estudio “ face to face” nuevos agentes (BOLERO-6 – el everolimus-exemestano y PEARL – palbociclib –exemestano ) vs QT( capecitabina )

FUTURO: SEGUIR INTEGRANDO LOS NUEVOS FÁRMACOS PARA CONSEGUIR > S CON CV

HER2esunoncogen“driver”encáncer

demama:“adicciónaloncogen”

HER2+

ENFERMEDAD HER-2

ENFERMEDAD HER-2 +

Ø  1ª Línea: Trastuzumab+ Pertuzumab + QT ( docetaxel ) > RO, PFS y SG vs Trastuzumab + QT (Cleopatra, A).

Ø  sustituir docetaxel por paclitaxel o vinorelbina puede ser una opción en algunas pacientes *

Ø  recaídas > 1 año tras adyuvancia con trastuzumab *

Ø  1ª Línea: Trastuzumab + Taxanos > PFS vs Lapatinib + taxanos ( MA.31, A).

Ø  1ª Línea pacientes HER-2 + RH + postmenopáusicas, IA+ antiHER-2 tanto trastuzumab ( Tandem, Electra) o lapatinib > RO y PFS vs IA , no impacto en SG ( B).

Baselga J, et al. N Engl J Med 2012 Gelmon KA et al. J Clin Oncol 2012 Kaufman B et al. J Clin 2009 Huober J et al. Breast 2012 Johnston S et al. J Clin Oncol 2009

Diseño Estudio CLEOPATRA

32

HER2-positive MBC centrally confirmed

(N = 808)

Placebo + trastuzumab

1:1 Docetaxel* ≥ 6 cycles

n = 406

n = 402

Pertuzumab + trastuzumab

Docetaxel* ≥ 6 cycles

PD

PD

Baselga J, et al. N Engl J Med 2012; 366:109–119.

•  Randomization stratified by geographic region and neo/adjuvant chemotherapy

•  Study dosing q3w: –  Pertuzumab/placebo: 840 mg loading → 420 mg maintenance –  Trastuzumab: 8 mg/kg loading → 6 mg/kg maintenance –  Docetaxel: 75 mg/m2 → 100 mg/m2 escalation if tolerated

O.1ª:SLP

Significant improvement in median PFS and OS

Over

all su

rviva

l (%)

HR 0.68 p = 0.0002

0

40

60

80

100

20

0 10 20 30 40 50 60 70 Time (months)

PHT: 56.5 mo. Pla+HT: 40.8 mo.

D=15.7 mo.

Time (months)

HR=0.62 p<0.0001

0 10 20 30 40 0

40

60

80

100

20

Prog

ress

ion-fr

ee su

rviva

l (%)

PHT: 18.5 mo. Pla+HT: 12.4 mo.

D =6.1 mo.

Baselga,etal.NEnglJMed2003;Swain,etal.NEnglJMed2015

Resultados de Eficacia: SLP y SG

TR:80,2%vs69,3%(RC:5,5%yRP:74,6%)Medianadeduracióndelarespuesta:20,2vs12,5

ENFERMEDAD HER-2 +

Ø  2ª Línea: Beneficio en continuar el bloqueo con terapias antiHER-2 trás progresión a trastuzumab ( A).

Ø  2ª Línea: TDM1 > Lapatinib+ Capecitabina en RO, PFS y SG en pacientes pretratadas con trastuzumab ( Emilia, A).

Ø  progresión en los 1ºs seis meses de tto adyuvante con trastuzumab.

Von Minckwitz G et al. J Clin Oncol 2009 Verma S, et al. N Engl J Med 2012

Estudio EMILIA: Diseño Verma S, et al. N Engl J Med 2012

•  Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease

•  Primary endpoints: PFS by independent review, OS, and safety

•  Key secondary endpoints: PFS by investigator, ORR, DOR

1:1

HER2-posi8veLABCorMBC(N=980)

• Priortaxaneandtrastuzumab

• Progressiononmetasta8ctreatmentorwithin6monthsofadjuvanttreatment

PD

T-DM1

3.6mg/kgq3wIV

Capecitabine 1000 mg/m2 PO bid, days 1–14, q3w

+ Lapatinib

1250 mg/day PO qd

PD

O.1º: PFS , SG

496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0

Cap + Lap T-DM1

No. at risk by independent review:

Median (months)

No. of events

Cap + Lap 6.4 304 T-DM1 9.6 265 Stratified HR=0.650 (95% CI, 0.55, 0.77)

P<0.0001

0.0

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Prop

ortio

n pr

ogre

ssio

n-fr

ee

Time (months)

Unstratified HR=0.66 (P<0.0001).

EstudioEMILIA:SLP(porRevisoresIndependientes)VermaS,etal.NEnglJMed2012

496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5

Cap + Lap T-DM1

No. at risk: Time (months)

78.4% 64.7%

51.8%

85.2%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 0.0

0.2

0.4

0.6

0.8

1.0

Prop

ortio

n su

rviv

ing

Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

Median (months) No. of events Cap + Lap 25.1 182 T-DM1 30.9 149 Stratified HR=0.682 (95% CI, 0.55, 0.85); P=0.0006

EfficacystoppingboundaryP=0.0037orHR=0.727

EstudioEMILIA:SupervivenciaGlobalVermaS,etal.NEnglJMed2012

ENFERMEDAD HER-2 +

Ø  3ª Línea y sucesivas : Beneficio en continuar el bloqueo con terapias antiHER-2 trás progresión a 2 más líneas de tto previo anti HER-2 ( A).

Ø  3ª Línea y sucesivas: TDM1 puede considerarse un estándar en pacientes previamente tratados con terapia antiHER-2( trastuzumab, lapatinib; ( Th3resa, A ).

Ø  3ª Línea y sucesivas : Lapatinib + Capecitabina ( B)

Ø  3ª Línea y sucesivas: Lapatinib+ Trastuzumab > PFS y SG vs Lapatinib solo ( B, el beneficio es más notable en el subgrupo de RH-).

Krop IE et al. Lancet Oncol 2014 Geyer CE et al. N Engl J Med 2006 Blackwell KL et al. J Clin Oncol 2012

2

T-DM1c (optional

crossover)

•  Stra8fica8onfactors:Worldregion,numberofpriorregimensforadvancedBC,dpresenceofvisceraldisease

•  Co-primaryendpoints:PFSbyinves-gatorandOS•  Keysecondaryendpoints:ORRbyinves-gatorandsafety

PD

PD T-DM1

3.6 mg/kg q3w IV (n=400)

Treatment of physician’s choice

(TPC)b

(n=200)

HER2-positive (central) advanced BCa

(N=600)

≥2 prior HER2-directed therapies for advanced BC

Prior treatment with trastuzumab, lapatinib,

and a taxane

1

Estudio TH3RESA: Diseño

O. 1ª: PFS y SG

Krop IE et al. Lancet Oncol 2014

* TPC: 83,2% contenía terapia antiHER-2 ( 80,4% Trastuzumab

Final OS Analysis

TPC T-DM1

No. at risk Time (months)

40 34 28 22 16 12 2 0.0

0.2

0.4

0.6

0.8

1.0

0

Prop

ortio

n su

rviv

ing

TPC (n=198)

T-DM1 (n=404)

Median (months) 15.8 22.7 Stratified HR=0.68 (95% CI: 0.54–0.85)

P=0.0007 (Pre-specified crossing boundary: HR<0.748;

P<0.012)

4 6 8 10 14 18 20 24 26 30 32 36 38

0 6 39 62 80 107 168 198 150 131 122 115 93 68 66 59 51 28 16 1 0 0 25 132 179 226 280 388 404 368 347 321 298 251 207 192 167 164 84 54 12 2

Estudio TH3RESA: SLP : 3,3 vs 6,2 m HR=0,528 Análisis Final de SG ( SABC 2015)

Final OS AnalysisMedian follow-up 50 months (range 0–70 months)

OS

(%)

0102030405060708090

100

0 10 20 30 40 50 7060

Time (months)

HR 0.68 95% CI = 0.56, 0.84

p = 0.0002

Ptz + T + D

Pla + T + D

12810422626831837102391179230289350

n at riskPtz + T + DPla + T + D

402406

40.8 months

56.5months

ǻ 15.7 months

Swain, ESMO 2014

Enfermedad avanzada. Primera línea.

MARIANNE Study Design


365

367

363

Ellis, ASCO 2015

Progression-Free Survival by IRF


ORR: HT 67.9%, T-DM1 59.7%, T-DM1+P 64.2%DURATION OF RESPONSE: HT 12.5m, T-DM1 20.7m, T-DM1-P 21.2m

Ellis, ASCO 2015

• Although better tolerated, T-DM1 or T-DM1+P are not superior to TH, so THP remains the preferred first-line therapy for HER2+MBC.– Can we extrapolate the same results with THP for high risk patients

who will receive pertuzumab in the neoadjuvant (adjuvant) setting?

– Are the results of these trials applicable for patients developing metastatic disease after adjuvant treatment with trastuzumab?

– And the duration of targeted therapy for those responding?

• Can we combine Pertuzumab and Trastuzumab with other partners?– Other taxans? (PERUSE)

– Other chemotherapies? VNR? (VELVET, ORR 62.9 and 64%)

– Other biologics? TDM1? (MARIANNE negative)

Enfermedad avanzada

Unanswered questions...• T-DM1 has been established as a second-line or first-line in early

relapse demonstrating superiority in front of capecitabine + lapatinib. – Has T-DM1 the same benefit in second-line setting in patients who

have received pertuzumab and trastuzumab previously?

– Could neratinib replace lapatinib in the combination with capecitabine keeping in mind its toxicity?

• Trastuzumab + lapatinib might be an option from the third-line and beyond.– Have we to restrict this treatment only for patients with HR negative?

• After treatment with a trastuzumab-containing regimen, 10-15% of patients will develop CNS metastases despite systemic control.– Which the best treatment for these patients?

Enfermedad avanzada

Unanswered questions...

1st line

2nd line

3rd line Capecitabine + Lapatinib

QT + Trastuzumab

QT + Trastuzumab

Capecitabine + Lapatinib

Docetaxel + Trastuzumab + Pertuzumab

TDM1

4rd line and beyond

Lapatinib + Trastuzumab

TDM1

Early relapse

TDM1

TDM1Lapatinib + Trastuzumab

TREATMENT SCHEME

Enfermedad avanzadaSeah, JNCCN 2014

ESQUEMA DE TRATAMIENTO

Enfermedad Avanzada HER-2+

ENFERMEDAD HER-2 +

Cuestiones pendientes: Ø  Trastu/Pertu/Docetaxel el estándar en 1ª Línea;

Ø  ¿ que va a pasar con las que reciban el esquema en el escenario neaodyuvante?

Ø  ¿ son aplicables realmente estos datos a las que progresan tras

adyuvancia con trastuzumab? Ø  Interés en combinar con otras QT ( paclitaxel- PERUSE; vinorelbina-

VELVET), otros biológicos parece que no ( TDM-1_ MARIANNE negativo). Ø  Porqué falló TDM-1 en 1ª línea?

Ø Tiene TDM-1 en 2ª línea , el mismo beneficio en pacientes que han recibido pertuzumab y trastuzumab previamente? Ø El futuro de nuevas moléculas : Neratinib ( inh EGFR y HER-2)?.

ENFERMEDAD TRIPLE NEGATIVA

• Son “pocos” 10-20%• No tenemos diana• Enfermedad heterogénea: inter e intratumoral

• �ŽŶ�т�ƉƌĞƐĞŶƚĂĐŝŽŶĞƐ�ŚŝƐƚŽůſŐŝĐĂƐ, ductal…

• �ŽŶ�т�ĂůƚƐ�ŵŽůĞĐƵůĂƌĞƐ TP53, BRCA, PI3CA…

Leydy J, et al. APLM, 2014

��SURQyVWLFR

Correlación Fenotipo Molecular con Intrínseco

Quizás dividir en basales y no basales es SIMPLIFICAR demasiado

SI BIEN ESTA PROPIA HETEROGENEIDAD NOS PODRÍA SEVIR COMO PUNTO DE PARTIDA

PARA BUSQUEDA DE UN TRATAMIENTO MAS “PRECISO”

British Journal of Cancer (2014) 111, 1532–1541A Prat, A. Lluch, J Albanell et al

Ø  BASAL-1 Ø  BASAL-2 Ø  INMUNOMODULADOR Ø  MESENQUIMAL Ø  MESENQUIMAL STEM CELL Ø  LUMINAL RECEPTOR ANDROGÉNICO

Ø  BASAL Ø  CLAUDIN- LOW

BASAL-1 BASAL-2 INMUNOMODULADOR

MESENQUIMAL

MESENQ-STELLCELL

LUMINALRECEPTORANDROGENICO

Frecuenc 20-25% 10% 20% 20% 10% 10-15%

Histología DUCTAL DUCTAL R.MEDULARES,DUCTAL

METAPLASICOS

METAPLASICOS

APOCRINOS

Feno8poIntrínseco

BASAL BASAL,Her-2

BASAL,Her-2,luminal

CLAUDINLOW

BASAL,otros

HER-2ENRICHED

Biología AlteracreparacionDNAydivisioncel

AlteracSeñaldeFactorescrec:EGFR,Met,wint

Alteracdelaseñalizacióndelasvíasderespuestainmune

Alteracdelamo-lidad,transiciónEM,MatrizEC

SimilaraMesenquimal,conbajosnivelesdeproliferación

Alteraciónmetabolismohormonalyreceptorandrogénico

Opcionesvos

PLATINOS-PARP

-MTOR-FACTCRECIM

ANTIPD1/PDL1

-MTOR-SRC

-MOR-PI3K-MEK/GF

-An-andrógenos-PI3K

ENFERMEDAD TRIPLE NEGATIVA ( RH Y HER-2 -)

Ø  1ª Línea: Antraciclinas o Taxanos sobre todo sino lo recibieron en adyuvancia ( A); preferiblemente de forma secuencial *

Ø  Otras QT: PLATINOS

Ø Carboplatino es superior a docetaxel en TR y SLP en población BRCA mutada en estudio fase III TNT ( B).

Ø  Carboplatino + Gemcitabina es aceptada por la EMA y FDA en pacientes resistentes a antraciclinas y taxanos fase III TNBC ( B, medianas de PFS de 5 m y SG de 1 año).

Tutt A et al. Cancer Res 2014 O`Shaughnessy J et al. J Clin Oncol 2014


Ø  Otras QT en 1ª Línea : VINORELBINA Y CAPECITABINA , opción válida en pacientes tratadas con antraciclinas y taxanos ( B).

Ø  Biológicos en 1ª Línea : BEVACIZUMAB+ QT, > RO, PFS (B), opción válida.

Ø Mantenimiento: Añadir Capecitabina a Bevacizumab, tras un tto de inducción con Taxano-Bevacizumab mejora significativamente la SLP ( Imelda 11.9 vs 4,3 m) y SG ( 39 vs 23 ).

Xu Y-C et al. Breast J 2013 Chan A et al. Eur J Cancer 2009 Miller K et al. N Engl J Med 2007 Gligorov J et al. Lancet Oncol 2014

POBLACIÓN GLOBAL: SLP, TR

medianadeSLP:9.2vs.6.7mesesHR0.64(IC95%0.57-0.71)tasasderespuesta49%vs32%P<0,0001

Metaanalisis Miles D, Ann Oncol July 25, 2013

SG, ANÁLISIS POR SUBGRUPOS

Ø  En análisis exploratorios adicionales, en el subgrupo de pacientes Triple Negativo previamente tratados con taxanos se demostró un incremento significativo de la mediana de SG global de 10 meses (25,6 vs. 15,0 meses) en la terapia de combinación con Avastin, HR de 0,61 (IC del 95%, 0,40 a 0,94).

Miles D, Ann Oncol July 25, 2013

MilesD,AnnOncolJuly25,2013

IMELDA:Open-labelrandomisedphaseIII

trial

BEV15mg/kgd1q3w

Stra-fica-onfactors• ERstatus(posi-vevsnega-ve)• Visceralmetastasis(presentvsabsent)• Stabledisease/response/non-measurabledisease• LDHconcentra-on(≤1.5vs>1.5×ULN)

Previouslyuntreated

HER2-nega8veLR/mBC BEV15mg/kgd1+CAP

1000mg/m2bidd1‒14q3w

BEV15mg/kg+DOC75‒100mg/m2

d1q3w

CR, PR or SD

TreattoPD,unacceptabletoxicityor

withdrawalofconsent

3‒6 cycles

R

1:1

Gligorov J et al. Lancet Oncol 2014

Estrategiaú-l–mantenimientoenTN,no~os

HT

O1º: PFS desde la randomización

Es8m

ated

proba

bility

Timefromrandomisa8on(months)

Obje-voprimario:PFSdesdelarandomizaciónPFS desde el comienzo de la 1ªLínea: 16,4 m vs 8,6 m HR: 0,38 BEV

(N=94)BEV–CAP(N=91)

Events,n(%) 83(88) 69(76)

MedianPFS,months(95%CI)

4.3(3.9–6.8)

11.9(9.8–15.4)

Stra-fiedhazardra-o(95%CI)

0.38(0.27–0.55)

Stra-fied2-sidedlog-ranktest p<0.0001

0.2

0

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

4.3 11.9

No.atriskBEV–CAP 91 80 62 50 40 34 26 22 16

12 8 2 2 1 0BEV 94 60 40 20 17 11 9 6 2

2 1 1 1 1 0

Objetivo secundario: SG desde la randomización

BEV(N=94)

BEV–CAP(N=91)

Events,n(%) 53(56) 33(36)1-yearOSrate(%) 72 902-yearOSrate(%) 49 69Stra-fiedhazardra-o(95%CI)

0.43(0.26–0.69)

Stra-fied2-sidedlog-rank p=0.0003Median,months(95%CI) 23.7

(18.5–31.7) 39.0(32.3–NR)

Es8m

ated

proba

bility

Timefromrandomisa8on(months)

0.2

0

0.4

0.6

0.8

1.0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 4542

23.7 39.0

Ú-lenTNporriesgodeprogresiónprecoz

traspararQT


Ø  2ªLíneas y sucesivas : Capecitabina, Vinorelbina, Gemcitabina, Nab-paclitaxel, Adriamicina Liposomal y Eribulina , son opciones válidas.

Ø Estudio fase III, Eribulina no superior a capecitabina en PFS ni en

SG en población general, en pts pretratadas con antraciclinas y taxanos, pero la diferencia fue favorable en SG en TN.

Kaufman PA et al. J Clin Oncol 2015

Tipo Tumoral: Triple-negativo

Pooleddataanalysisstudy305&301

MedianOS(months)

Eribulin(n=243) 12.9

Control(n=185) 8.2

HR 0.741

95%CI 0.599,0.917

Pvalue 0.0056

Time (months) 12 14 16 18 20 22 24 58 10 8 6 4 2 0

134 81

154 98

173 120

201 139

226 168

243 185

28 17

24 16

32 19

40 23

54 28

60 33

88 45

73 38

108 59

122 67

1 1

0 0

1 1

4 2

3 1

5 3

5 3

Number of subjects at risk

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56

9 3

7 3

9 3

13 6

10 5

17 8

20 9

Pro

porti

on o

f sur

viva

l

4.7monthsdifference


Cuestiones pendientes con nuevos agentes: Ø  El papel de la Inmunoterapia ( Pembrolizumab; Atezolizumab+ Nabpaclitaxel)

Ø  El papel de los antiandrógenos ( Enzalutamida)

Ø  El papel de los inhibidores del PARP

En definitiva, ahondar en el conocimiento, definiendo las dianas de cada uno de los

subtipos.

Gracias !

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