faculty presenterprograms.rmei.com/mbc354vl/slides.pdfongoing 1st line pertuzumab phase iii study...

StateState--ofof--thethe--ArtArtTreatments in Oncology : Treatments in Oncology :

Clinical Cases inClinical Cases inMetastatic Breast CancerMetastatic Breast Cancer

Faculty Presenter

Stefan Gluck, MD, PhDStefan Gluck, MD, PhDProfessor of MedicineProfessor of Medicine

Clinical DirectorClinical Director

BramanBraman Family Breast Cancer InstituteFamily Breast Cancer Institute

University of Miami Miller School of MedicineUniversity of Miami Miller School of Medicine

Miami, FloridaMiami, Florida

Disclosure of Conflicts of Interest

Stefan Gluck, MD, PhD, has an affiliation with Stefan Gluck, MD, PhD, has an affiliation with AgendiaAgendia, Amgen, , Amgen, CelgeneCelgene, Eisai, Genentech, , Eisai, Genentech, and Pfizer (and Pfizer (ConsultantConsultant, , SpeakerSpeaker’’s Bureaus Bureau, , ResearchResearch); and Bristol); and Bristol--Myers Squibb Myers Squibb ((ConsultantConsultant, , SpeakerSpeaker’’s Bureaus Bureau).).

Learning Objectives

•• Select optimal therapies based upon hormone Select optimal therapies based upon hormone receptor status and human epidermal growth receptor status and human epidermal growth factor receptor expressionfactor receptor expression

•• Apply evidenceApply evidence--based treatment strategies based treatment strategies including hormonal, chemotherapy, and including hormonal, chemotherapy, and targeted agents alone or in combinationtargeted agents alone or in combination

•• Individualize treatment regimens based upon Individualize treatment regimens based upon extent of metastatic disease and patient extent of metastatic disease and patient symptoms, quality of life, and performance symptoms, quality of life, and performance statusstatus

Activity Overview

•• This activity consists of three sections, each with a This activity consists of three sections, each with a clinical caseclinical case

•• AntiAnti--HER2 Treatment for Advanced Breast CancerHER2 Treatment for Advanced Breast Cancer•• Advances in Chemotherapy for Advanced Breast Advances in Chemotherapy for Advanced Breast

CancerCancer•• Endocrine Resistance in Advanced Breast CancerEndocrine Resistance in Advanced Breast Cancer

MBC Survival by Decade

Giordano SH, et al. Giordano SH, et al. CancerCancer. 2004;100(1):44. 2004;100(1):44--52.52.

NCCN Guidelines for Invasive Breast CancerPREFERRED CHEMOTHERAPY REGIMENS FOR RECURRENT OR METASTATIC BREAST

CANCERSINGLE AGENTSAnthracyclines•Doxorubicin•Epirubicin•Pegylated lipsomal doxorubicinTaxanes•Paclitaxel•Docetaxel•Albumin-bound paclitaxelAnti-metabolites•Capecitabine•GemcitabineOther mircotubule inhibitors•Vinorelbine•Eribulin

OTHER SINGLE AGENTS•Cyclophosphamide•Mitozantrone•Cisplatin•Etoposide (po) ( category 2B)•Vinblastine•Fluorouracil Cl•Ixabepilone

AGENTS WITH BEVACIZUMAB•Paclitaxel

CHEMOTHERAPY COMBINATIONS•CAF/FAC (cyclophosphamide/doxorubicin/fluorouracil)•FEC (fluorouracil/epirubicin/cyclophosphamide)•AC (doxorubicin/cyclophosphamide)•EC (epirubicin/cyclophosphamide•AT (doxorubicin/docetaxel; doxorubicin/paclitaxel)•CMF (cyclophosphamide/methotrexate/fluorouracil)•Docetaxel/capecitabine•GT (gemcitabine/paclitaxel)

OTHER COMBINATIONS•Ixabepilone + capecitabine (category 2B)

FIRST-LINE AGENTS FOR HER2-POSITIVE DISEASETrastuzumab with:•Paclitaxel +/- carboplatin•Docetaxel•Vinorelbine•Capecitabine

AGENTS FOR TRASTUZUMAB-EXPOSED HER2-POSITIVE DISEASE•Lapatinib + capecitabine•Trastuzumab + other first-line agents•Trastuzumab + capecitabine•Trastuzumab + lapatinib (without cytotoxic therapy)

Targeted Treatments of HER2+ Breast Cancer

Do we need chemotherapy or

other targeted Rx?

How to define trastuzumab

resistance? Is mTOR a good

target?

Optimal delivery: with trastuzumab,

T-DM1?

In combination with Trastuzumab

Lapatinib Pertuzumab

TDM-1Everolimus

Trastuzumab

HER2 Dimerization is key to Signaling Activity

HER2HER2 HER3HER3

PPP

P

PhosphorylationPhosphorylation of the tyrosine of the tyrosine kinasekinase domain by HER2 initiates intracellular signalingdomain by HER2 initiates intracellular signaling

LigandLigand--activated activated

HER2:HER3 HER2:HER3 dimerdimer

Ferguson KM, et al. Ferguson KM, et al. Mol CellMol Cell. 2003;11:507. 2003;11:507--517. 517. OlayioyeOlayioye MA, et al. MA, et al. EMBO JEMBO J. 2000;19:3159. 2000;19:3159--3167.3167.Hynes NE, et al. Hynes NE, et al. Nat Rev CancerNat Rev Cancer. 2005;5:341. 2005;5:341--354. 354. RowinskyRowinsky EK. EK. AnnuAnnu Rev MedRev Med. 2004;55:433. 2004;55:433--457457

Pertuzumab Clinical Experience•• Development ObjectiveDevelopment Objective

•• Does Does pertuzumabpertuzumab add significant efficacy when added to add significant efficacy when added to trastuzumabtrastuzumab??

•• Over 1000 patients treated to dateOver 1000 patients treated to date

•• MBC with prior HER2 directed therapyMBC with prior HER2 directed therapy

•• Relapsed locally advanced breast cancer / previously untreated Relapsed locally advanced breast cancer / previously untreated HER2+ MBCHER2+ MBC

•• Ongoing studies:Ongoing studies:

•• 11stst Line Phase III study (CLEOPATRA)Line Phase III study (CLEOPATRA)

•• NeoadjuvantNeoadjuvant Phase II study (NEOSPHERE)Phase II study (NEOSPHERE)

•• NeoadjuvantNeoadjuvant Phase II study (TRYPHAENA)Phase II study (TRYPHAENA)Safety of Safety of pertuzumabpertuzumab & & trastuzumabtrastuzumab in combo with in combo with anthracyclinesanthracyclines

•• 22ndnd Line study (PHEREXA)Line study (PHEREXA)CapecitabineCapecitabine + + trastuzumabtrastuzumab +/+/-- pertuzumabpertuzumab

Ongoing 1st Line PertuzumabPhase III Study (CLEOPATRA)

Enrollment completed midEnrollment completed mid--20102010

Data Availability 2011Data Availability 2011

Randomized 1:1, 2-Arm, Open-Label, Multicenter Trial

Primary Efficacy Endpoint:Primary Efficacy Endpoint: PFS PFS

1:1 1:1 randomizationrandomization

TrastuzumabTrastuzumab + + docetaxeldocetaxel + + pertuzumabpertuzumab

Trastuzumab + docetaxel +

placebo

First line HER2+ mBCOr recurrent locally

advanced pts(n=800)

T-DM1 in Combo with Pertuzumab

00

300300

600600

900900

12001200

00 1010 2020 3030 4040 5050

Tu

mo

r V

olu

me

(mm

Tu

mo

r V

olu

me

(mm

33 ))m

ean

+/

mea

n +

/ --se

mse

m

Time (days)Time (days)TmabTmab--MCCMCC--

DM1 (IV)DM1 (IV)

PertuzumabPertuzumab (IP)(IP)

KPLKPL--4 breast tumor 4 breast tumor xenograftxenograft modelmodelData on file.

PertuzumabPertuzumab 15 mg/kg15 mg/kg

VehicleVehicleTmabTmab--MCCMCC--DM1DM1 + + pertuzumabpertuzumab

TmabTmab--MCCMCC--DM1DM1 1 mg/kg1 mg/kg

Preliminary Efficacy Promising Preliminary Efficacy Promising with Twith T--DM1 + DM1 + PertuzumabPertuzumab

•• 67 patients enrolled67 patients enrolled•• 44 evaluable relapsed pts (2nd line or beyond)44 evaluable relapsed pts (2nd line or beyond)•• 22 pts with newly diagnosed HER2+ MBC (first22 pts with newly diagnosed HER2+ MBC (first--line)line)•• 1 pt without safety data, excluded from analysis1 pt without safety data, excluded from analysis•• Median 5 doses TMedian 5 doses T--DM1 receivedDM1 received

•• ORR 35.7% (10/28 partial responses)ORR 35.7% (10/28 partial responses)

•• ORR data from 28 pts who received ORR data from 28 pts who received ≥≥4 cycles, or4 cycles, orprogressed or diedprogressed or died

Cohort 1 (n=3)Cohort 1 (n=3) Cohort 2 (n=25)Cohort 2 (n=25) Total (N=28)Total (N=28)

Complete responseComplete response 00 00 00

Partial responsePartial response 2 (66.7)2 (66.7) 8 (32.0)8 (32.0) 10 (35.7)10 (35.7)

Stable diseaseStable disease 1 (33.3)1 (33.3) 12 (48.0)12 (48.0) 13 (46.4)13 (46.4)

Progressive diseaseProgressive disease 00 4 (16.0)4 (16.0) 4 (14.3)4 (14.3)

MissingMissing 00 1 (4.0)1 (4.0) 1 (3.6)1 (3.6)

Miller K, et al. Miller K, et al. J J ClinClin OncolOncol. . 2010;28:7s. Abstract 1012.2010;28:7s. Abstract 1012.

What are Antibody-Drug Conjugates (ADCs)?

ADCsADCs areare monoclonalmonoclonal antibodiesantibodies toto whichwhich aa potentpotentcytotoxiccytotoxic drugdrug isis conjugatedconjugated

ADC

Preferential delivery of potent cytotoxic agent to tumor cells via tumor-specific and/or over-expressed cell surface antigens

Increase drug Reduce normal-tissue drug exposure

Improved therapeutic window

T-DM1•• TrastuzumabTrastuzumab--DM1 (TDM1 (T--DM1) is a novel antiDM1) is a novel anti--HER2 antibody HER2 antibody

drugdrug––conjugate in development for the treatment of conjugate in development for the treatment of HER2HER2--positive metastatic breast cancer (MBC)positive metastatic breast cancer (MBC)1,21,2

•• Combines the HER2Combines the HER2--targeting properties of targeting properties of trastuzumabtrastuzumab33 with targeted delivery of a highly potent with targeted delivery of a highly potent antianti--microtubule derivative, DM1microtubule derivative, DM133--55

•• After binding to HER2, TAfter binding to HER2, T--DM1 undergoes receptorDM1 undergoes receptor--mediated internalization,mediated internalization,66 resulting in intracellular resulting in intracellular release of DM1release of DM1

1. 1. KropKrop I, et al. I, et al. J J ClinClin OncolOncol. . 2008;28:26982008;28:2698--2704.2704.2. Burris HA, et al. 2. Burris HA, et al. J J ClinClin OncolOncol.. 2010; in press.2010; in press.3. Lewis Phillips, et al. 3. Lewis Phillips, et al. Cancer ResCancer Res. 2008;68:9280. 2008;68:9280--9290.9290.

4 . 4 . JunttilaJunttila TT, et al. TT, et al. Breast Cancer Res Treat.Breast Cancer Res Treat. 2011;128:3472011;128:347--356.356.5. 5. RemillardRemillard S, et al. S, et al. Science.Science. 1975;189:10021975;189:1002––1005.1005.6. Austin CD, et al. 6. Austin CD, et al. Mol Mol BiolBiol Cell. Cell. 2004;15(12):52682004;15(12):5268––5282.5282.

Phase III T-DM1 vs Capecitabine + Lapatinib in HER2+ MBC (EMILIA)

KeyKey inclusioninclusion criteriacriteriaPriorPrior treatmenttreatment toto includeinclude aa taxanetaxane andand trastuzumabtrastuzumab inin adjuvant,adjuvant,locallylocally advancedadvanced oror metastaticmetastatic settingsettingDocumentedDocumented progressionprogression ofof diseasedisease duringduring oror afterafter treatmenttreatment forfor advanced/advanced/metastaticmetastatic diseasedisease oror withinwithin 66 monthsmonths ofof completingcompleting adjuvantadjuvant therapytherapy

Primary end points:Primary end points: OS, OS, PFS by IRF, SafetyPFS by IRF, SafetySecondary end points:Secondary end points: quality of lifequality of life

HER2+ HER2+ (centrally confirmed)(centrally confirmed)Locally advanced or Locally advanced or

MBC previously receivedMBC previously receivedtrastuzumabtrastuzumab--based based

therapytherapy(n = 580)(n = 580)

TT--DM1DM1(3.6 mg/kg) q3w(3.6 mg/kg) q3w

LapatinibLapatinib(1250 mg/day) Days 1(1250 mg/day) Days 1––21 21 ++

CapecitabineCapecitabine(1000 mg/m(1000 mg/m22) Days 1) Days 1––14 q3w14 q3w

EA Perez,EA Perez,11 L Dirix,L Dirix,22 J Kocsis,J Kocsis,33 L Gianni,L Gianni,44 J Lu,J Lu,55 J Vinholes,J Vinholes,66 V Ng,V Ng,77

C Linehan,C Linehan,77 S Agresta,S Agresta,77 S HurvitzS Hurvitz88

11Mayo Clinic, Jacksonville, FL, USA; Mayo Clinic, Jacksonville, FL, USA; 22SintSint--Augustinus Hospital, Antwerp, Belgium; Augustinus Hospital, Antwerp, Belgium; 33Semmelweis University Hospital, Budapest, Hungary; Semmelweis University Hospital, Budapest, Hungary; 44Istituto Istituto NazionaleNazionale deidei TumoriTumori, , Milan, Italy; Milan, Italy; 55Division of Hematology and Oncology, State University of New YorDivision of Hematology and Oncology, State University of New York at k at Stony Brook, Stony BrookStony Brook, Stony Brook,, NY, USA; NY, USA; 66Clinica de Clinica de OncologiaOncologia de Porto de Porto AlegreAlegre, , BrasilBrasil; ;

77Genentech, Inc., South San Francisco, CA, USA; Genentech, Inc., South San Francisco, CA, USA; 88UCLA Translational Oncology UCLA Translational Oncology Research International, Los Angeles, CA, USAResearch International, Los Angeles, CA, USA

Perez EA, et al. Perez EA, et al. AbstrAbstr LBA3. ESMO 2010LBA3. ESMO 2010

New Data: TDM4450New Data: TDM4450

Efficacy and Safety of TrastuzumabEfficacy and Safety of Trastuzumab--DM1 DM1 vsvs TrastuzumabTrastuzumab plus plus DocetaxelDocetaxelin HER2+ MBC Patients with No Prior in HER2+ MBC Patients with No Prior Chemotherapy for Metastatic DiseaseChemotherapy for Metastatic Disease

• Randomized, phase II, international, open-label study• HER2-positive, measurable disease required• Stratification factors

• World region, prior adjuvant trastuzumab therapy, disease-free interval • Primary endpoints: PFS by INV, safety• Key secondary endpoints: ORR, clinical benefit, OS, QOL, symptom control

T-DM1 vs (Docetaxel + Trastuzumab): Study Design

1:1 1:1 HER2HER2--positive, positive, recurrent locally recurrent locally advanced BC or advanced BC or

MBC (n=137)MBC (n=137)

T-DM13.6 mg/kg Q3W until PD

Trastuzumab8 mg/kg dose; 6 mg/kg Q3W

+ Docetaxel75 or 100 mg/m2 Q3W

CrossoverT-DM1PDPD


Safety Conclusions:T-DM1 vsDocetaxel + Trastuzumab

• T-DM1 appears to have a favorable overall safety profile compared with trastuzumab + docetaxel in 1st line MBC• Incidence of Grade ≥3 AEs in the T-DM1 arm

• Half that in the trastuzumab + docetaxel arm• 37% vs 75%

• No grade 3 neutropenia; only 1.5% alopecia• T-DM1 was not associated with an increased

risk of cardiotoxicity compared with trastuzumab + docetaxel


Efficacy Conclusions:T-DM1 vsDocetaxel + Trastuzumab

•• Encouraging preliminary ORR resultsEncouraging preliminary ORR results•• 47.8% for T47.8% for T--DM1 DM1 vsvs 41.4% for 41.4% for trastuzumabtrastuzumab + +

docetaxeldocetaxel by investigator assessment, by investigator assessment, although confidence intervals overlapalthough confidence intervals overlap•• Final analysis of PFS (1ary endpoint) in Final analysis of PFS (1ary endpoint) in

20122012

•• These data support phase III evaluation of TThese data support phase III evaluation of T--DM1 as 1stDM1 as 1st--line therapy for HER2+ MBCline therapy for HER2+ MBC


1st Line MBC Phase III MARIANNEStudy: BO22589/TDM 4788g

HER2+ recurrent locally advanced HER2+ recurrent locally advanced or untreated MBCor untreated MBC

1ary endpoints:1ary endpoints: OS, PFS as assessed by IRF; SafetyOS, PFS as assessed by IRF; Safety2ary endpoints:2ary endpoints: PFS by investigator; PRO analyses; BiomarkersPFS by investigator; PRO analyses; BiomarkersSuperiority design with a NonSuperiority design with a Non--inferiority analysis between each of inferiority analysis between each of the experimental arms and the control armthe experimental arms and the control armInterim futility analysis:Interim futility analysis: Option to drop experimental armOption to drop experimental arm

Trastuzumab + taxane (until PD)n=364

T-DM1 + pertuzumab (until PD)n=364

TT--DM1 + pertuzumab placebo DM1 + pertuzumab placebo (until PD)(until PD)

n=364n=364

Central HER2+Patients stratified by:

World region

Neo/Adjuvant therapy (Y/N)

Trastuzumab based therapy (Y/N)

Visceral disease (Y/N)

n=1092n=1092

Global Steering CommitteeGlobal Steering Committee

Other Markers to Optimize anti-HER2 Rx in N9831, etc

•• SABCS 2010SABCS 2010•• CC--mycmyc gene, protein gene, protein ------ additional data additional data

•• TMAsTMAs, whole slides, whole slides

•• ASCO 2011ASCO 2011•• PTEN, IGFPTEN, IGF--R1R1

•• After ASCO 2011After ASCO 2011•• MultigeneMultigene predictor using DASLpredictor using DASL•• p95p95•• HER3 using AQUA HER3 using AQUA

•• New translational R01 to evaluate immune parametersNew translational R01 to evaluate immune parameters

•• Collaborators (with EAP)Collaborators (with EAP)•• ReinholzReinholz, , DueckDueck, , EckelsEckels, , AndorferAndorfer, Thompson, Hillman, , Thompson, Hillman,

RimmRimm, Knutson, , Knutson, ClynesClynes, Jenkins, Geiger, McCullough, , Jenkins, Geiger, McCullough, ChenChen

Breast Cancer: Resistance to Trastuzumab

Breast Cancer Cells Can Become Breast Cancer Cells Can Become Resistant to Resistant to TrastuzumabTrastuzumab by a by a Variety of MechanismsVariety of Mechanisms

•• Excess HER2Excess HER2•• HER2 HER2 dimerizationdimerization with other with other

receptorsreceptors•• IGFIGF--1R signaling1R signaling•• Loss of down regulation of Loss of down regulation of

PTENPTEN•• Activating mutations in PI3K Activating mutations in PI3K

or or AktAkt•• Truncated receptor (p95)Truncated receptor (p95)

NahtaNahta R, et al. R, et al. Nat Nat ClinClin PractPract OncolOncol. 2006;3:269. . 2006;3:269. NahtaNahta R, R, EstevaEsteva FJ. FJ. Breast Cancer ResBreast Cancer Res. 2006;8:215.. 2006;8:215.Hynes NE, et al. Hynes NE, et al. Nat Rev CancerNat Rev Cancer. 2005;5:341. 2005;5:341--354. Lu CH, et al. 354. Lu CH, et al. ClinClin Cancer ResCancer Res. 2007;13:5883.. 2007;13:5883.

Everolimus May Partially Overcome Trastuzumab Resistance

ReceptorReceptorsignaling signaling

Constitutive activation ofConstitutive activation ofdownstream pathways downstream pathways

Increased signaling throughIncreased signaling throughIGFIGF--1R1R

Constitutive PI3K/AKT activationConstitutive PI3K/AKT activation

Elevated AKT or Elevated AKT or pAKTpAKT

Absent or low PTENAbsent or low PTEN

Truncated HERTruncated HER--2 (p95)2 (p95)

Downstream inhibition withDownstream inhibition witheverolimuseverolimus counters counters

resistance mechanismsresistance mechanisms

AngiogenesisAngiogenesis

mTORmTOR

AKTAKT

AMPKAMPKTSC1TSC1 TSC2TSC2

PTENPTENLKB1LKB1

Cell growth andCell growth andproliferationproliferation

Cell metabolismCell metabolism

PI3KPI3K

RHEBRHEB

IGFIGF‐‐1R1R EGFR/HER2EGFR/HER2NutrientsNutrients

EverolimusEverolimus

The PI3K/AKT/mTOR PathwayThe PI3K/AKT/mTOR Pathway

•• mTORmTOR (mammalian(mammaliantargettarget ofof rapamycinrapamycin))signalingsignaling playsplays aa keykeyrolerole inin

•• CCellell growthgrowth•• CCellell proliferationproliferation•• RegulationRegulation ofof

•• ApoptosisApoptosis•• AngiogenesisAngiogenesis•• LymphocytesLymphocytes•• HomeostasisHomeostasis•• MetabolismMetabolism

Protein productionProtein production

AKTAKT

4E4E--BP1BP1

PI3KPI3K

PTENPTEN

S6

S6K1S6K1

elFelF--4E4E

Cell growthCell growthand proliferationand proliferation


mTORmTOR

Oxygen, Oxygen, energy, and energy, and

nutrientsnutrients

TSC2TSC2 TSC1TSC1

Growth factors including Growth factors including IGFIGF--1, VEGF, 1, VEGF, ErbBErbB

Estrogen Estrogen receptorreceptor

Ras/RafRas/Rafpathway pathway kinaseskinases

Nutrient uptake Nutrient uptake and metabolismand metabolism

BOLERO-1: 1st LinePaclitaxel + Trastuzumab ±

EverolimusEverolimus 10.0 mg PO daily

Paclitaxel 80 mg/m2 IV on days 1, 8, 15

Trastuzumab 2 mg/kga IV on days 1, 8, 15, 22

Placebo PO daily

Paclitaxel 80 mg/m2 IV on days 1, 8, 15

Trastuzumab 2 mg/kg IV on days 1, 8, 15, 22

R

•• Patients with HER2+ Patients with HER2+ unresectableunresectable locally advanced, locally advanced, recurrent, or MBC; no prior therapy for locally advanced recurrent, or MBC; no prior therapy for locally advanced or recurrent disease except hormonal therapyor recurrent disease except hormonal therapy

•• Stratification by prior adjuvant or Stratification by prior adjuvant or neoadjuvantneoadjuvanttrastuzumabtrastuzumab; visceral metastases; visceral metastases

N=717N=717

2:12:1((everolimus:placeboeverolimus:placebo))

AVEREL: 1st-Line Bevacizumab + Trastuzumab in HER2+ MBC

•• Primary endpoint: PFSPrimary endpoint: PFS•• Other endpoints: OS, PFS assessed by independent Other endpoints: OS, PFS assessed by independent

review facility, ORR, duration of response, time to review facility, ORR, duration of response, time to treatment failure, QOL, safety treatment failure, QOL, safety

aa100 mg/m100 mg/m22

Treat to disease Treat to disease progressionprogression

DocetaxelDocetaxelaa + + TrastuzumabTrastuzumab

DocetaxelDocetaxelaa + + TrastuzumabTrastuzumab + + BevacizumabBevacizumab15 mg/kg q3w15 mg/kg q3w

PreviouslyPreviouslyuntreated untreated

HER2HER2--positive positive LR/MBCLR/MBCn=410n=410

Landscape in 1Landscape in 1stst Line HER2+ MBCLine HER2+ MBC

2010 201320122011 20152009 2014 2016 2019 >2020

NeratinibNeratinib

TT‐‐DM1DM1

PertuzumabPertuzumab

BevacizumabBevacizumab

LapatinibLapatinib

EverolimusEverolimus

MARIANNE: T+H vs T‐DM1 vs T‐DM1 + pertuzumab

CLEOPATRA: TH vs TH+P

AVEREL: TH vs TH+ Avastin®

EGF104535: T vs TL

EGF108919: TH vs T+ lapatinib

EGF104383: TH vs TH + lapatinib

BOLERO 1: TH vs TH + everolimus

TH vs T + neratinib

HER2+ Clinical Case

52 52 y.oy.o. postmenopausal female . postmenopausal female dxdx. with 3 cm. node . with 3 cm. node positive (12 of 15 excised) HER 2 3+ by IHC, ER and positive (12 of 15 excised) HER 2 3+ by IHC, ER and PR 0 in 2005PR 0 in 2005

•• Treated with lumpectomy, AC, followed by weekly Treated with lumpectomy, AC, followed by weekly paclitaxelpaclitaxel with with traztuzumabtraztuzumab x12 then radiation along x12 then radiation along with completion of 1 yr. of with completion of 1 yr. of traztuzumabtraztuzumab in 2006in 2006

•• Well until 2010 when she developed RUQ pain, PET Well until 2010 when she developed RUQ pain, PET showed 5 liver metastases, normal liver enzymes, showed 5 liver metastases, normal liver enzymes, ECOG performance status = 1ECOG performance status = 1

•• Biopsy showed recurrent breast cancer, HER 2 3+ by Biopsy showed recurrent breast cancer, HER 2 3+ by IHC, ER and PR 0IHC, ER and PR 0

•• What are the management options for this patient?What are the management options for this patient?

SingleSingle--Agent Agent vsvs Combination Combination FrontFront--Line Chemotherapy for MBCLine Chemotherapy for MBC

•• Response rate Response rate favors combinationfavors combination

•• TTP TTP favors combinationfavors combination

•• Survival Survival ??

•• Toxicity Toxicity favors single agentfavors single agent

•• Quality of life Quality of life ??

Few combination trials using investigational drugs truly tested Few combination trials using investigational drugs truly tested the the hypothesis of combination versus sequential singlehypothesis of combination versus sequential single--agent therapy.agent therapy.

Recent Example of Single-Agent vs Combination Trials

Clinical TrialClinical Trial Median TTP Median TTP ((mosmos))

Overall Overall Survival Survival

((mosmos))

Grade IV Grade IV NeutropeniaNeutropenia (%)(%)

AlbainAlbain et al. (N = 529)et al. (N = 529)

PaclitaxelPaclitaxel

PaclitaxelPaclitaxel + + gemcitabinegemcitabine

2.92.9

5.25.2

15.815.8

18.518.577

1717

OO’’ShaughnessyShaughnessy et al. (N = 511)et al. (N = 511)

DocetaxelDocetaxel

DocetaxelDocetaxel + + capecitabinecapecitabine

4.24.26.16.1

11.511.514.514.5

11111212

AlbainAlbain KS.KS. JJ NatlNatl CancerCancer Inst.Inst. 2004;96(24):18012004;96(24):1801--1804.1804.

OO’’ShaughnessyShaughnessy,, etet al.al. JJ ClinClin OncolOncol.. 2002;20(12):28122002;20(12):2812--2823.2823.

New Agents

•• EpothilonesEpothilones

•• EribulinEribulin

O

O

O

OH

H O

O

OO

OCH3

CH3

CH3

OHOCCH3

CH3

R2O

NHR1

2’

OH

OH

CH3

CH3CH3CH3

CH3

CH3

O

O

O O

R

S

N

RR11 RR22

PaclitaxelPaclitaxel:: PhenylPhenyl AcetylAcetylDocetaxelDocetaxel:: tt--ButanolButanol HH

EpothiloneEpothilone A:A: R = HR = HEpothiloneEpothilone B:B: R = CH3R = CH3

EpothilonesEpothilones and and TaxanesTaxanes

•• Differ structurally, and bind to completely different sites on Differ structurally, and bind to completely different sites on tubulintubulin

•• EpothilonesEpothilones are not affected by many of the resistance mechanisms are not affected by many of the resistance mechanisms caused by caused by taxanestaxanes

1.1. GoodinGoodin S,S, etet al.al. JJ ClinClin OncolOncol.. 2004;22(10):20152004;22(10):2015--2025.2025.2.2. GiannakakouGiannakakou P,P, etet al.al. ProcProc NatlNatl AcadAcad SciSci UUSASA.. 2000;97(6):29042000;97(6):2904--2909.2909.

Agent Patients, n

Population Schedule ORR, %

PFS, Mos

DLT

KOS 861

(EPO D)29

Anthraresistant

100 mg/m2 over 90 mins 3 out of

4 wks14 2.5

Neuro G3/418.5%

ZK-EPO2 65Anthra

resistant≤ 3 regimens

16-22 mg/m2 IV q3w

9 1.5Neuro G3/4

25%

Patupilone3

(EPO B)36

Progressive brain mets

10 mg/m2

q3wNR CNS 2.8

Neuro G3/4 5%

Diarrhea G3 30%

Epothilones in Development for Breast Cancer

1.1. BuzdarBuzdar A, et al. A, et al. Breast Cancer Res TreatBreast Cancer Res Treat. 2005;94(Suppl 1):S69. Abstract #1087.. 2005;94(Suppl 1):S69. Abstract #1087.2.2. Morrow PH, et al. Morrow PH, et al. J J ClinClin OncolOncol. 2009;27(Suppl):15S. Abstract 1083.. 2009;27(Suppl):15S. Abstract 1083.3. Murphy C, et al. 3. Murphy C, et al. ASCO Breast Cancer Symposium.ASCO Breast Cancer Symposium. 2009:Abstract 234.2009:Abstract 234.

Epothilone B

Ixabepilone

OH

OH

CH3

CH3CH3CH3

CH3

CH3

O

O

O O

CH3

S

N

OH

OH

CH3

CH3CH3CH3

CH3

CH3

O

NH

O O

CH3

S

N

Ixabepilone

•• Epothilone B: Epothilone B: Natural macrolide antibiotic Natural macrolide antibiotic produced by myxobacterium produced by myxobacterium Sorangium cellulosum Sorangium cellulosum

•• Ixabepilone: Ixabepilone: Semisynthetic epothilone B Semisynthetic epothilone B analog (azaanalog (aza--epothilone B)epothilone B)

Goodin S, et al. Goodin S, et al. J Clin OncolJ Clin Oncol. 2004;22(10):2015. 2004;22(10):2015--2025.2025.

Progressive Lines of TherapyProgressive Lines of Therapy

1842

35

12

41

18

5035

22

57

26

00

2020

4040

6060

8080

Pat

ien

ts (

%)

Pat

ien

ts (

%)

Objective ResponseObjective Response Stable DiseaseStable Disease

MBC TaxaneMBC Taxane--

ResistantResistant55MBC MBC

MultiresistantMultiresistant(Anthra/Tax/ (Anthra/Tax/

Cape)Cape)66

NeoadjuvantNeoadjuvantT2T2--4, N04, N0--3, 3,

M0M011

After Adjuvant After Adjuvant

61

PretreatedPretreated44

(n=37)(n=37)AnthraAnthra22

(n=29)(n=29)AnthraAnthra33

(n=65)(n=65)

Pathologic Complete ResponsePathologic Complete Response100100

1.1. BaselgaBaselga J,J, etet al.al. JJ ClinClin OncolOncol.. 2009;27(4):5262009;27(4):526--534.534.2.2. DenduluriDenduluri N,N, etet al.al. JJ ClinClin OncolOncol.. 2007;25(23):34212007;25(23):3421--3427.3427.3.3. RochRochéé H,H, etet al.al. JJ ClinClin OncolOncol.. 2007;25(23):34152007;25(23):3415--3420.3420.

Clinical Activity of Ixabepilone Clinical Activity of Ixabepilone Monotherapy in Breast CancerMonotherapy in Breast Cancer

4.4. LowLow JA,JA, etet al.al. JJ ClinClin OncolOncol.. 2005;23(12):27262005;23(12):2726--2734.2734.5.5. ThomasThomas E,E, etet alal.. JJ ClinClin OncolOncol.. 2007;25(23):33992007;25(23):3399--3406.3406.6.6. PerezPerez EA,EA, etet al.al. JJ ClinClin OncolOncol.. 2007;25(23):34072007;25(23):3407--3014.3014.

046 046 -- PFSPFS

048 048 -- OSOS

Primary EndpointsPrimary EndpointsIxabepilone +Ixabepilone +capecitabinecapecitabine

CapecitabineCapecitabine

Ixabepilone Phase III StudiesIxabepilone Phase III Studies•• Phase III studies: 046 (N=752)Phase III studies: 046 (N=752)11 and 048 (N= and 048 (N=

1,221)1,221)22

–– DoubleDouble--refractory patientsrefractory patients

MBC patients with MBC patients with prior prior

anthracycline anthracycline and taxane Txand taxane Tx

1. Thomas ES, et al. 1. Thomas ES, et al. J Clin OncolJ Clin Oncol. 2007;25(33):5210. 2007;25(33):5210--5217.5217.2. Hortobagyi GN, et al. 2. Hortobagyi GN, et al. ASCO Breast Cancer Symposium. ASCO Breast Cancer Symposium. 2008: Abstract 186. 2008: Abstract 186.

Impact of Ixabepilone on PFSImpact of Ixabepilone on PFS

•• Consistent superiority in prolonging PFS with Consistent superiority in prolonging PFS with ixabepilone combination over capecitabine alone in ixabepilone combination over capecitabine alone in both phase III studiesboth phase III studies


Parameter

0461 0482

Ixa + Cape(n=375)

Cape(n=377)

Ixa + Cape(n=480)

Cape(n=480)

Median PFS,* mos (95% CI)

5.3(4.2–5.59)

3.8(2.86–4.17)

6.2(5.59–6.77)

4.4( 4.14–5.42)

HR (95% CI)

0.78 (0.67–0.91)

0.79(0.69–0.90)

P value 0.0011 0.0005

Impact of Ixabepilone on ORRImpact of Ixabepilone on ORR

•• ORR for the combination arm was superior to ORR for the combination arm was superior to capecitabine monotherapycapecitabine monotherapy


Response

0461 0482

Ixa + Cape(n=375)

Cape(n=377)

Ixa + Cape(n=462)

Cape(n=462)

ORR, % (95% CI)

42.1(37.1–47.3)

22.5(18.4–27.1)

43.3(38.7–47.9)

28.8(24.7–33.2)

P value 0.0001 0.0001

Best response achieved, %

• CR 3 1 3 2

• PR 39 22 40 26

• SD 36 38 37 39

Adverse Event (AE)

0461 0482

Ixa + Cape(n=369)

Cape(n=368)

Ixa + Cape(n=595)

Cape (n=603)

Exposure, median no. of cycles

5 4 6 5

Neutropenia 68 11 73 8

Leukopenia 57 6 63 7

Anemia 10 4 5 4

Thrombocytopenia 8 4 6 3

Febrile neutropenia 4 1 4 2

Grade 3/4 TreatmentGrade 3/4 Treatment--Related Related Hematologic Adverse EventsHematologic Adverse Events


Adverse Event

046[1] 048[2]

Ixa + Cape(n=369)

Cape(n=368)

Ixa + Cape(n=595)

Cape(n=603)

Exposure, median no. of cycles 5 4 6 5

Peripheral neuropathy, % 23 0 24 1

Resolution of neuropathy,* median wks (range)

6.0 (4.6–7.6)

--6.2

(5.0–8.7)--

Hand-foot syndrome, % 18 17 21 20

Fatigue, % 9 3 12 3

Diarrhea, % 6 9 7 9

Myalgia, % 8 <1 5 0

Toxic deaths, % 3 <1 <1 <1

Arthralgia, % 3 0 3 0

Stomatitis, % 1 1 2 1

GradeGrade 3/43/4 TreatmentTreatment--RelatedRelatedHematologicHematologic AdverseAdverse EventsEvents (cont(cont’’d)d)


SummarySummary

•• Ixabepilone plus capecitabine demonstrates Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in superior efficacy to capecitabine alone in MBC resistant to anthracyclines and taxanesMBC resistant to anthracyclines and taxanes–– Improvement of PFS in both studiesImprovement of PFS in both studies

–– Statistically significant increase in ORR Statistically significant increase in ORR •• Study 046: 42.1% vs 22.5%Study 046: 42.1% vs 22.5%

•• Study 048: 43.3% vs 28.8%Study 048: 43.3% vs 28.8%

–– Improved median OSImproved median OS

•• Manageable safety profile (normal or Grade 1 Manageable safety profile (normal or Grade 1 LFTs)LFTs)

Jordan MA, et al. Jordan MA, et al. Mol Cancer TherMol Cancer Ther. 2005;4(7):1086. 2005;4(7):1086--1095.1095.

Eribulin Mesylate (E7389): Eribulin Mesylate (E7389): A Novel Tubulin Targeted AgentA Novel Tubulin Targeted Agent

•• SyntheticSynthetic analoganalog ofofhalichondrinhalichondrin B;B; naturalnaturalproductproduct fromfrom marinemarine spongespongeHalichondriaHalichondria okadaiokadai

•• NovelNovel chemicalchemical structurestructure

•• UniqueUnique effecteffect onon microtubulemicrotubuledynamicsdynamics–– BlocksBlocks microtubulemicrotubule

polymerizationpolymerization

–– NoNo effecteffect onondepolymerizationdepolymerization

–– SequestersSequesters tubulintubulin intointononfunctionalnonfunctional aggregatesaggregates

305305 StudyStudy –– EEisaiisai MMetastaticetastatic BrBreasteast CancerCancer StudyStudyAAssessingssessing PhysicianPhysician’’ss CChoicehoice versusversus EE73897389

Primary EndpointsPrimary Endpoints•• Overall survivalOverall survival

Secondary EndpointsSecondary Endpoints•• PFSPFS•• ORRORR•• DoRDoR•• SafetySafety

Twelves C, et al. Twelves C, et al. J Clin Oncol. J Clin Oncol. 2010; 28(18Suppl): Abstract CRA1004.2010; 28(18Suppl): Abstract CRA1004.

EMBRACE StudyEMBRACE Study

Trial DesignTrial Design•• OpenOpen--label, label,

multicenter studymulticenter study•• N=762N=762•• Locally advanced or Locally advanced or

MBCMBC•• 22––5 prior 5 prior

chemotherapies chemotherapies ((≥≥2 for advanced 2 for advanced disease)disease)

•• Prior anthracycline Prior anthracycline and taxaneand taxane

•• Refractory to mostRefractory to mostrecent chemotherapyrecent chemotherapy

TreatmentTreatmentEribulin MesylateEribulin Mesylate

1.4 mg/m1.4 mg/m22, 2, 2--5 min IV bolus5 min IV bolusDays 1 and 8 of 21Days 1 and 8 of 21--day cycleday cycle

PhysicianPhysician’’ss choicechoiceAnyAny monotherapymonotherapy

(cytotoxic,(cytotoxic, hormonal,hormonal, biologicbiologicoror supportivesupportive carecare only)only)

RND 2:1

13.12

3.7 4.1

10.65

2.3

6.7

0022446688

101012121414161618182020

Median OSMedian OS Median PFSMedian PFS Median DoRMedian DoR

Mon

ths

Mon

ths

EribulinEribulin

TPC=Rx of TPC=Rx of Physicians Physicians ChoiceChoice

P=0.04

P=0.09

P=0.005

Phase III EMBRACE Study Phase III EMBRACE Study of Eribulin in MBCof Eribulin in MBC


Eribulin (%) TPC (%)

ORR* 12 5

CR 0.4 0

PR 11.5 5

EMBRACE Outcomes:EMBRACE Outcomes:Objective Response RatesObjective Response Rates


* * PP = 0.005= 0.005

Parameter Eribulin Monotherapy (%)

Asthenia/fatigue 7.6

Neutropenia 44

Peripheral neuropathy 8.4

Treatment-related serious AE 12

Phase III EMBRACE Study:Phase III EMBRACE Study:Grade 3/4 Adverse EventsGrade 3/4 Adverse Events


SummarySummary

•• Primary endpoint: median OSPrimary endpoint: median OS–– Eribulin arm demonstrated an improvement over TPC Eribulin arm demonstrated an improvement over TPC

arm with statistical significancearm with statistical significance

•• Secondary endpointsSecondary endpoints–– ORR was statistically significantORR was statistically significant

•• 12% vs 5% (12% vs 5% (PP=0.005)=0.005)

–– PFS was supportive of the primary endpoint but did not PFS was supportive of the primary endpoint but did not reach statistical significancereach statistical significance

•• 3.7 months vs 2.3 months (3.7 months vs 2.3 months (PP=0.04)=0.04)

•• Manageable tolerability profile was reconfirmedManageable tolerability profile was reconfirmed

Chemotherapy Clinical Case Chemotherapy Clinical Case 53 y.o. African American female presents with progressive diseas53 y.o. African American female presents with progressive disease e

after initial dx. of breast cancer 5 yrs. ago (Stage 1; ER/PR/HEafter initial dx. of breast cancer 5 yrs. ago (Stage 1; ER/PR/HER2R2--))

•• Rx. history includes doxorubicin, cyclophosphamide, and Rx. history includes doxorubicin, cyclophosphamide, and radiation radiation

•• Rx. history after recurrence includes docetaxel/capecitabineRx. history after recurrence includes docetaxel/capecitabine

•• The patient presents with progression after secondThe patient presents with progression after second--line therapyline therapy


----goals of therapy including prolonged survival, goals of therapy including prolonged survival,

symptom palliationsymptom palliation

----options for third line treatment, dosing/schedulingoptions for third line treatment, dosing/scheduling

----supportive care implicationssupportive care implications

Endocrine Resistance in Endocrine Resistance in Advanced Breast CancerAdvanced Breast Cancer

Strong Evidence Links Hormone Resistance to Cross-Talk Between Signal Transduction

Pathways and ER Signalling

Cell proliferationCell proliferation

mTOR

MEKMEK

RASRAS

ERKERK

RAFRAF

PI3KPI3K

AKTAKT

TSC2TSC2 TSC1TSC1

ERER

ERER

IGFIGF--1R, EGFR1R, EGFR

EE

EREREE

mTORmTOR

Yue W. Yue W. J Steroid Biochem Mol Biol. J Steroid Biochem Mol Biol. 2007;106:1022007;106:102--110.110.

ER and HER2•• Crosstalk between Crosstalk between

ER and HER family ER and HER family membersmembers

•• ER can ER can upregulate HER2 upregulate HER2 and stimulate and stimulate downstream downstream signalingsignaling

•• HERHER--dependent dependent phosphorylation phosphorylation promotes ER promotes ER signalingsignaling

•• Implication: dual Implication: dual ER/HER2 inhibitionER/HER2 inhibition

TAnDEM Trial

•• Phase III results:Phase III results:•• Randomized 207 Randomized 207

patients topatients toanastrozole (A) aloneanastrozole (A) alonevs A + trastuzumab (T)vs A + trastuzumab (T)

•• PFS=3.8 mo. for A vs PFS=3.8 mo. for A vs 5.6 mo. for A + T; 5.6 mo. for A + T; HR=0.63 HR=0.63 (95% CI: 0.47(95% CI: 0.47--0.84)0.84)

•• Grade 3 and 4 AEs: Grade 3 and 4 AEs: 23% and 5%, A + T; 23% and 5%, A + T; 15% and 1%, A alone15% and 1%, A alone

Kaufman B, et al. Kaufman B, et al. J Clin Oncol. J Clin Oncol. 2009;27:55292009;27:5529--5537.5537.

EGF 30008: Phase III Trial•• N=219N=219

•• Letrozole (L) vs. Letrozole (L) vs. L + lapatinib (Lap)L + lapatinib (Lap)

•• PFS PFS •• 3.0 mo L vs3.0 mo L vs

8.2 mo L + Lap; 8.2 mo L + Lap; HR=0.65 HR=0.65 (95% CI: 0.47(95% CI: 0.47--0.89)0.89)

•• OS (<50% events)OS (<50% events)•• 32 mo. vs 33 32 mo. vs 33

mo.mo.•• QOLQOL

•• No differenceNo difference

Johnston S, et al. Johnston S, et al. J Clin Oncol. J Clin Oncol. 2009;27:55382009;27:5538--5546. 5546.

Other Combinations Targeting EGFR/HER2

•• Fulvestrant +/Fulvestrant +/-- lapatinib (phase III, CALGB lapatinib (phase III, CALGB 40302, Burstein et al, SABCS 2010)40302, Burstein et al, SABCS 2010)

•• Enrolled pts with HER2 1Enrolled pts with HER2 1--3+, ER+ MBC 3+, ER+ MBC pretreated with Aispretreated with Ais

•• No benefit in ITT populationNo benefit in ITT population•• PFS better in HER2+ subgroup (5.9 v 2.8 PFS better in HER2+ subgroup (5.9 v 2.8

mo)mo)•• Toxicity increasedToxicity increased

•• Anastrozole +/Anastrozole +/-- gefitinib (Cristofanilli, 2008)gefitinib (Cristofanilli, 2008)•• 93 pts: PFS 14.5 vs 8.2 mo, HR 0.5593 pts: PFS 14.5 vs 8.2 mo, HR 0.55•• Increased toxicity in combination armIncreased toxicity in combination arm

The PI3K/AKT/mTOR Pathway

•• mTORmTOR (mammalian(mammalian targettargetofof rapamycin)rapamycin) signalingsignalingplaysplays aa keykey rolerole inin

•• CCellell growthgrowth•• CCellell proliferationproliferation•• RRegulationegulation ofof

•• AApoptosispoptosis•• AngiogenesisAngiogenesis•• LymphocytesLymphocytes•• HomeostasisHomeostasis•• MetabolismMetabolism

Protein productionProtein production

AKTAKT

4E4E--BP1BP1

PI3KPI3K

PTENPTEN

S6S6

S6K1S6K1

elFelF--4E4E

Cell growthCell growthand proliferationand proliferation


mTORmTOR

Oxygen, Oxygen, energy, and energy, and

nutrientsnutrients

TSC2TSC2 TSC1TSC1

Growth factors including Growth factors including IGFIGF--1, VEGF, ErbB1, VEGF, ErbB

Estrogen Estrogen receptorreceptor

Ras/Raf Ras/Raf pathway pathway kinaseskinases

Nutrient uptake Nutrient uptake and metabolismand metabolism

1. Bjornsti MA, et al. 1. Bjornsti MA, et al. Nat Rev CancerNat Rev Cancer. 2004;34(5):335. 2004;34(5):335--348. 2. Crespo JL, et al. 348. 2. Crespo JL, et al. Microbiol Mol Biol RevMicrobiol Mol Biol Rev. 2002;66(4):579. 2002;66(4):579--591. 591. 3. Huang S, et al. 3. Huang S, et al. Cancer Biol TherCancer Biol Ther. 2003;2(3):222. 2003;2(3):222--232. 4. Mita MM, et al. 232. 4. Mita MM, et al. Clin Breast Cancer.Clin Breast Cancer. 2003;4(2):1262003;4(2):126--137.137.5. Wullschleger S, et al. 5. Wullschleger S, et al. Cell. Cell. 2006;124(3):4712006;124(3):471--484. 484. 6. Johnston SR. 6. Johnston SR. Clin Cancer ResClin Cancer Res. 2005;11(2 Pt 2):889S. 2005;11(2 Pt 2):889S--899S. 899S.

Inhibiting mTOR in Hormone Receptor Positive Breast Cancer: Rationale

•• Everolimus (RAD001)Everolimus (RAD001)•• Oral inhibitor of mTOROral inhibitor of mTOR•• Approved for renal cell carcinoma and SEGA (US)Approved for renal cell carcinoma and SEGA (US)

•• In vitro activity in hormoneIn vitro activity in hormone--resistant modelresistant model

•• Modest single agent activityModest single agent activity

•• Increases antitumor activity of neoadjuvant letrozole Increases antitumor activity of neoadjuvant letrozole (Baselga et al, JCO 2009)(Baselga et al, JCO 2009)

•• Selected pretreated patients with MBCSelected pretreated patients with MBC•• Increase the number of patients whose tumors Increase the number of patients whose tumors

might be drive by activation of PI3K/ACT/mTOR might be drive by activation of PI3K/ACT/mTOR pathwaypathway

TAMRAD: a Randomized Phase II trial of TAMRAD: a Randomized Phase II trial of Everolimus with Tam vs Tam alone in HR+ Everolimus with Tam vs Tam alone in HR+

MBC with Prior Exposure to AIsMBC with Prior Exposure to AIs

•• Randomized Phase II, 111 PM women with MBCRandomized Phase II, 111 PM women with MBC

•• Prior exposure to AI, prior adj tam or chemo okPrior exposure to AI, prior adj tam or chemo ok

•• Stratification: Primary or secondary hormone resistanceStratification: Primary or secondary hormone resistance•• Primary: Relapse during adjuvant AI, progression within 6 Primary: Relapse during adjuvant AI, progression within 6

months of starting AI treatment in metastatic settingmonths of starting AI treatment in metastatic setting•• Secondary: Late relapse (Secondary: Late relapse (≥≥6 months) or prior response and 6 months) or prior response and

subsequent progression to metastatic AI treatmentsubsequent progression to metastatic AI treatment

•• No crossover plannedNo crossover planned

•• Median followMedian follow--up 22 months, median age 63up 22 months, median age 63--6666

B : Tamoxifen 20 mg/d + RAD001 10 mg/d (TAM + RAD) B : Tamoxifen 20 mg/d + RAD001 10 mg/d (TAM + RAD)

A : Tamoxifen, 20 mg/d (TAM)A : Tamoxifen, 20 mg/d (TAM)

Bachelot et al. SABCS 2010.Bachelot et al. SABCS 2010.

Primary Endpoint: Clinical Benefit Ratepp = 0.045 (exploratory analysis)= 0.045 (exploratory analysis)

00

1010

2020

3030

4040

5050

6060

7070

TAMTAM TAM + RADTAM + RAD

CB

R,

% o

f P

atie

nts

CB

R,

% o

f P

atie

nts

42.1%42.1%(29.1(29.1––55.9)55.9)

61.1%61.1%(46.9(46.9––74.1)74.1)

More stomatitis, fatigue, rash, anorexia and diarrhea on combinaMore stomatitis, fatigue, rash, anorexia and diarrhea on combination armtion arm28% (15) dose reduced due to AE on combination arm28% (15) dose reduced due to AE on combination arm

Time to Progression As a Function of Intrinsic Hormone Resistance

•• PrimaryPrimary hormone hormone resistance (n = 54)resistance (n = 54)

–– TAM: 3.9 mo.TAM: 3.9 mo.

–– TAM + RAD: 5.4 mo.TAM + RAD: 5.4 mo.

–– HR = 0.74 (0.42HR = 0.74 (0.42––1.3) 1.3)

•• SecondarySecondary hormonehormoneresistanceresistance (n(n == 56)56)

–– TAM:TAM: 5.05.0 mo.mo.

–– TAMTAM ++ RAD:RAD: 17.417.4 mo.mo.

–– HRHR == 0.380.38 (0.21(0.21––0.71)0.71)

TAM TAM

TAM + RAD TAM + RAD

0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91.01.0

00 66 1212 1818 2424 3030

Pro

babi

lity

of S

urv

ival

Pro

babi

lity

of S

urv

ival

Pro

babi

lity

of S

urv

ival

Pro

babi

lity

of S

urv

ival

MonthsMonths

0.00.00.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.91.01.0

MonthsMonths00 66 1212 1818 2424 3030

Ongoing Trial of Everolimus in ER+ Ongoing Trial of Everolimus in ER+ Advanced Breast Cancer Advanced Breast Cancer –– BOLERO 2BOLERO 2

•• N = 705 pts with ERN = 705 pts with ER++ BC refractory to LET or ANABC refractory to LET or ANA

•• Study has completed accrualStudy has completed accrual

SCREEN

SSCCRREEEENN

Placebo 10 mg PO dailyPlacebo 10 mg PO daily+ exemestane+ exemestane

RandomizeRandomize2:1*2:1*

Inhibitors of PI3K-AKT-mTOR Signaling in Clinical Development

Engelman. Engelman. Nat Rev Cancer. Nat Rev Cancer. 2009;9:5502009;9:550--562562

ERα and IGF Signaling

•• IGFIGF receptorsreceptors andand adaptoradaptor proteinsproteins areareestrogenestrogen responsiveresponsive genesgenes

•• ERERαα functionfunction isis enhancedenhanced byby IGFIGF receptorreceptoractivationactivation

•• InIn primaryprimary breastbreast cancer,cancer, ERERαα andand IGF1RIGF1Rareare frequentlyfrequently coco--expressedexpressed

•• InsulinInsulin receptorreceptor genegene amplificationamplification hashasbeenbeen seenseen inin endocrineendocrine resistantresistant breastbreastcancercancer

Phase II: AMGPhase II: AMG--479 (MoAb to IGF1R) With 479 (MoAb to IGF1R) With Exemestane or Fulvestrant in HR+ MBCExemestane or Fulvestrant in HR+ MBC

•• Randomized 2:1Randomized 2:1•• AMGAMG--479 (12 mg/kg Q2 weeks) or placebo + 479 (12 mg/kg Q2 weeks) or placebo +

exemestane 25 mg/d or fulvestrant 500 mg exemestane 25 mg/d or fulvestrant 500 mg day 1, 250 mg days 15 & 29, then Q4 weeksday 1, 250 mg days 15 & 29, then Q4 weeks

•• Crossover allowed on disease progressionCrossover allowed on disease progression

•• Metastatic, postmenopausal women with HR+ Metastatic, postmenopausal women with HR+ MBC in second line settingMBC in second line setting

•• Results (Kaufman et al, 2010)Results (Kaufman et al, 2010)•• No improvement in PFS, ORR or CBR with No improvement in PFS, ORR or CBR with

addtion of AMGaddtion of AMG--479479•• 3.9 vs 5.7 m0, HR 1.173.9 vs 5.7 m0, HR 1.17

Kaufman PA, et al. SABCS 2010. Abstract S1Kaufman PA, et al. SABCS 2010. Abstract S1--4.4.

Anti-IGF DrugsTyrosine kinase inhibitorsTyrosine kinase inhibitors

AEW541AEW541 NovartisNovartis PreclinicalPreclinicalBMSBMS--754807754807 BMSBMS Phase IPhase IInsmInsm--18 (NDGA)18 (NDGA) InsmedInsmed Phase I/IIPhase I/IIXLXL--228228 ExelixisExelixis PreclinicalPreclinicalOSIOSI--906906 OSIOSI Phase IPhase IGSK 1904529AGSK 1904529A GSKGSK PreclinicalPreclinicalABDPABDP AZAZ PreclinicalPreclinicalAA--928605928605 AbbottAbbott PreclinicalPreclinicalAXL1717 (PPP)AXL1717 (PPP) AlexarAlexar Phase IPhase I

Monoclonal antibodiesMonoclonal antibodiesA12 (cixutumumab)A12 (cixutumumab) ImCloneImClone Phase I/IIPhase I/II FH IgG1FH IgG1AVE1642AVE1642 sanofisanofi--aventisaventis d/cd/c Hum IgG1Hum IgG1Sch717454 (robatumumab)Sch717454 (robatumumab) ScheringSchering Phase I/IIPhase I/II FH IgG1FH IgG1MK 0646 (dalotuzumab)MK 0646 (dalotuzumab) MerckMerck Phase IIPhase II Hum IgG1Hum IgG1AMG 479AMG 479 AmgenAmgen Phase IIPhase II FH IgG1FH IgG1R 1507 R 1507 RocheRoche d/cd/c FH IgG1FH IgG1BIIB022BIIB022 Biogen IdecBiogen Idec Phase IPhase I FH IgG4FH IgG4h10H5h10H5 GenentechGenentech PreclinicalPreclinical Hum IgG1Hum IgG1Neutralizing antibodyNeutralizing antibodyMEDIMEDI--573573 MedImmuneMedImmune Phase IPhase I FH IgG2FH IgG2

Di Cosimo, et al. ASCO, 2010. Abstract #3008

Di Cosimo, et al. ASCO, 2010. Abstract #3008.

Di Cosimo, et al. ASCO, 2010. Abstract #3008.

Randomized, Open Label, Phase II Study for Randomized, Open Label, Phase II Study for Treatment of ER+ MBC After Progression on a Treatment of ER+ MBC After Progression on a

NonNon--steroidal AIsteroidal AI

Combined Src and Aromatase Inhibition Impairs Growth of Human Breast Cancer

Chen Y, et al. Chen Y, et al. Clin Cancer ResClin Cancer Res. 2009;15(10):3396. 2009;15(10):3396--3405.3405.

Clinical Trials Clinical Trials

•• Letrozole +/Letrozole +/-- dasatinib (USON)dasatinib (USON)•• Exemestane +/Exemestane +/-- dasatinib (BMS)dasatinib (BMS)•• Fulvestrant + dasatinib + dalotuzumab (4 arm trial, MDACC)Fulvestrant + dasatinib + dalotuzumab (4 arm trial, MDACC)

↑↑ VEGF Predicts Resistance to FirstVEGF Predicts Resistance to First--line Endocrine Therapy in MBCline Endocrine Therapy in MBC

Manders P, et al. Manders P, et al. Cancer . 2Cancer . 2003;98:2125003;98:2125--2132.2132.

PFS PFS N=96N=96

ER/PRER/PR VEGFVEGF--highhigh VEGFVEGF--lowlow

negativenegative 10%10% 13%13%

positivepositive 38%38% 73%73%

Response rateResponse rate

Ryden L, et al. Ryden L, et al. J Clin OncolJ Clin Oncol. 2005;23:4695. 2005;23:4695--4704.4704.

VEGFR2 grade 0 to 2 tumors VEGFR2 grade 3 tumors

Lack of Benefit for Tam in ER+ Breast Cancer in Tumors with ↑ VEGFR2 (IHC)

Letrozole + BevacizumabMSKCC/UCSF Phase 2 Feasibility Study

••Primary endpoint: toxicityPrimary endpoint: toxicity

••Secondary endpoints: TTP, RR, SD>6 mo.Secondary endpoints: TTP, RR, SD>6 mo.

••Prior NSPrior NS--AI allowed if no documented progressionAI allowed if no documented progression

••Ovarian suppression allowed (medical or surgical)Ovarian suppression allowed (medical or surgical)

2.5 mg orally each day2.5 mg orally each day

WeekWeek 00 33 66 99

BevacizumabBevacizumab15 mg/kg IV15 mg/kg IV

LetrozoleLetrozole

1122

Traina, et al. ASCO 2006. Abstract 3050.Traina, et al. ASCO 2006. Abstract 3050.

Endocrine Therapy: Tamoxifen or Aromatase Inhibitor (letrozole)Endocrine Therapy: Tamoxifen or Aromatase Inhibitor (letrozole)DoubleDouble--blind, placeboblind, placebo--controlled controlled Primary Endpoint: ProgressionPrimary Endpoint: Progression--free Survivalfree SurvivalCirculating tumor and endothelial cells measured during treatmenCirculating tumor and endothelial cells measured during treatmentt

PI: DicklerPI: Dickler

CALGB 40503: FirstCALGB 40503: First--line line Endocrine Rx +/Endocrine Rx +/-- BevacizumabBevacizumab

ER or PR+ER or PR+

MBCMBC

1st line Rx1st line Rx

+/+/-- MeasurableMeasurable

PostPost--Menopausal or Menopausal or

Ovarian suppressionOvarian suppression Endocrine therapy + PlaceboEndocrine therapy + Placebo

Endocrine therapy + BevacizumabEndocrine therapy + Bevacizumab

(15mg/kg IV q3wks)(15mg/kg IV q3wks)

Proteins Proteins modulated by modulated by

DACsDACs

DeDe--acetylation of nonacetylation of non--histone proteins histone proteins regulates key processes in cancer cellsregulates key processes in cancer cells

DAC depicts individual deacetylases, e.g. HDAC1, HDAC4, HDAC6DAC depicts individual deacetylases, e.g. HDAC1, HDAC4, HDAC6

Histone

DACDAC DACDAC

-tubulin HSP90HIF-1

DACDAC DACDAC DACDAC

Tumour Tumour suppressor gene suppressor gene

activity activity

Loss of tumour Loss of tumour suppressor suppressor

functionfunction

Microtubule Microtubule depolymerisation/ depolymerisation/

aggresome aggresome formationformation

VEGF VEGF Oncoproteins Oncoproteins Downstream Downstream

effectseffects

CellCell--cycle cycle arrestarrest

ApoptosisApoptosis

Cell motility Cell motility and invasionand invasion

Cell proliferation Cell proliferation and survivaland survival


Tumour Tumour effectseffects

p53

Deacetylase Inhibitors and Deacetylase Inhibitors and Rationale for CombinationsRationale for Combinations

•• Deacetylase inhibitors:Deacetylase inhibitors:•• Panobinostat (LBH 589)Panobinostat (LBH 589)•• Valproic acidValproic acid•• Vorinostat (SAHA)Vorinostat (SAHA)

•• Histone deacetylases (HDAC) play a Histone deacetylases (HDAC) play a central role in transcriptional regulation central role in transcriptional regulation

•• Inhibition of HDAC may restore sensitivity Inhibition of HDAC may restore sensitivity to antito anti--hormonal therapy by modulation of hormonal therapy by modulation of estrogen and progesterone receptors estrogen and progesterone receptors

Phase II Trial: Tamoxifen and Vorinostat for Heavily Pre-Treated HR+ MBC

•• ResponseResponse•• Objective response, CR/PRObjective response, CR/PR 5/ 24 (21%)5/ 24 (21%)•• Stable Disease Stable Disease >> 12 mo 12 mo 1 / 24 ( 4%)1 / 24 ( 4%)•• Stable Disease > 3 moStable Disease > 3 mo 7 / 24 (29%) 7 / 24 (29%)

•• ToxicityToxicity•• Thrombocytopenia, fatigue, diarrhea, Thrombocytopenia, fatigue, diarrhea,

anorexia/weight loss of low gradeanorexia/weight loss of low grade•• One DVT/PEOne DVT/PE

•• Correlative studiesCorrelative studies•• H3 and H4 acetylation seen in PBMCs, PK and H3 and H4 acetylation seen in PBMCs, PK and

additional correlative data underadditional correlative data under

•• 43 patients enrolled, final data pending43 patients enrolled, final data pending

Munster, et al. ASCO 2008.Munster, et al. ASCO 2008.

Phase II: LowPhase II: Low--dose or Highdose or High--dose dose Estradiol for HR+ MBCEstradiol for HR+ MBC

•• Randomized:Randomized: eestradiolstradiol 66 mg/daymg/day(physiological)(physiological) oror 3030 mg/daymg/day(high(high dose)dose)

•• Postmenopausal,Postmenopausal, ER+ER+ and/orand/or PR+PR+ MBC,MBC,priorprior AIAI ((≥≥2424 weeksweeks PFS)PFS)oror relapserelapse afterafter >2>2 yearsyears adjuvantadjuvant AIAI

•• FDGFDG PETPET atat baselinebaseline andand atat 2424 hourshours totoassessassess metabolicmetabolic flareflare asas predictorpredictor ofofresponseresponse

•• Objective:Objective: CBRCBR (CR+PR+SD(CR+PR+SD ≥≥66 months)months)Ellis MJ, et al. SABCS 2008. Abstract 16.Ellis MJ, et al. SABCS 2008. Abstract 16.

Phase II: LowPhase II: Low--dose or Highdose or High--dose dose Estradiol for HR+ MBC Estradiol for HR+ MBC –––– EfficacyEfficacy

•• PET Flare predictive of response PET Flare predictive of response (P<0.0001)(P<0.0001) Estradiol 6 mg Estradiol 6 mg

(N=34)(N=34)Estradiol 30 mg Estradiol 30 mg

(N=32)(N=32)

CRCR 00 00

PR, %PR, % 99 33

SDSDaa, %, % 2020 2525

PD, %PD, % 6262 5050

NANAbb, %, % 99 2222

CBR, %CBR, % 2929 2828

a=At least 24 weeks; b=Not Assessed due to early withdrawal due a=At least 24 weeks; b=Not Assessed due to early withdrawal due to toxicity.to toxicity.

Ellis MJ, et al. Ellis MJ, et al. JAMAJAMA. 2009;302(7):774. 2009;302(7):774--780.780.

Endocrine Therapy Clinical Case

58 y.o. female dx. with left T1N1 ER+, PR58 y.o. female dx. with left T1N1 ER+, PR--, HER2 , HER2 --, IDC , IDC

•• Rx. history includes doxorubicin/cyclophosphamide Rx. history includes doxorubicin/cyclophosphamide followed by paclitaxel. After completing chemotherapy followed by paclitaxel. After completing chemotherapy she started anastrozole she started anastrozole

•• She developed low back pain and was found to have She developed low back pain and was found to have bony metastases 3 yrs. after starting anastrozolebony metastases 3 yrs. after starting anastrozole

•• She was changed to exemestane with improvement in She was changed to exemestane with improvement in pain, then progression with new vertebral and rib pain, then progression with new vertebral and rib lesions by 9 mos. lesions by 9 mos.

•• She was then rx. with fulvestrant with symptomatic She was then rx. with fulvestrant with symptomatic response, 8 mos. after starting she developed new response, 8 mos. after starting she developed new bone disease and 3 liver lesionsbone disease and 3 liver lesions


Thank You Thank You

faculty presenterprograms.rmei.com/mbc354vl/slides.pdfongoing 1st line pertuzumab phase iii study...

Documents