ana maria gonzalezana maria gonzalez--angulo, …ana maria gonzalezana maria gonzalez--angulo, m.d....

HER2+ breast cancer:HER2+ breast cancer:Progress and PromisesProgress and Promises

Ana Maria GonzalezAna Maria Gonzalez--Angulo, M.D.Angulo, M.D.Associate ProfessorAssociate ProfessorAssociate ProfessorAssociate Professor

Breast Medical OncologyBreast Medical OncologySystems BiologySystems Biology

ProgressProgress

•• Dual targeting of HER2 is better than Dual targeting of HER2 is better than HERHER--2 targeting single agents2 targeting single agents–– the evolving story with the evolving story with trastuzumabtrastuzumab//pertuzumabpertuzumab

–– role for role for trastuzumabtrastuzumab//lapatiniblapatinib–– role for role for trastuzumabtrastuzumab//lapatiniblapatinib

–– role for role for trastuzumabtrastuzumab//bevacizumabbevacizumab ??

•• DDuration of effective treatmenturation of effective treatment–– role in MBCrole in MBC

–– role in adjuvant ?role in adjuvant ?

PPertuzumabertuzumab and and trastuzumabtrastuzumab target target different HER2 receptor domainsdifferent HER2 receptor domains

HER2HER2

PertuzumabPertuzumab

HER1/3/4HER1/3/4

TrastuzumabTrastuzumab

DimerizationDimerizationdomaindomain

Subdomain IVSubdomain IV

TrastuzumabTrastuzumab::

•• Inhibits ligandInhibits ligand--independent HER2 independent HER2 signalingsignaling

•• Activates ADCCActivates ADCC

•• Prevents HER2 ECD sheddingPrevents HER2 ECD shedding

PertuzumabPertuzumab::

•• Inhibits ligandInhibits ligand--dependent HER2 dependent HER2 dimerization and signalingdimerization and signaling

•• Activates ADCCActivates ADCC

KPL-4

400

450

500

550

600

650[m

m3 ] ±

SE

M

Vehicle control

Pertuzumab (30/15 mg/kg/w i.p.)

Trastuzumab (30/15 mg/kg/w i.p.)

PertuzumabPertuzumab + + trastuzumabtrastuzumabcombination in a HER2combination in a HER2--positive positive breast cancer breast cancer xenograftxenograft modelmodel

0

50

100

150

200

250

300

350

400

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80Treatment period [d]

Mea

n tu

mor

vol

ume

[

Pertuzumab + Trastuzumab

6/10 animals cured

Friess et al. ESMO 2006

KPL-4

900

1000

1100

1200

1300

1400

[mm

3 ] ± S

EM

Vehicle control

Trastuzumab (15 mg/kg/w i.p.)

Trastuzumab + Pertuzumab

PertuzumabPertuzumab in a breast cancer in a breast cancer xenoxeno--graft model progressing under graft model progressing under

trastuzumabtrastuzumab alonealone

Unpublished data: W. Scheuer, Roche Pharma Research Penzberg

0

100

200

300

400

500

600

700

800

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85Treatment period [d]

Mea

n tu

mor

vol

ume

[

Phase II trial of Phase II trial of pertuzumabpertuzumab + + trastuzumabtrastuzumab in in HER2HER2--positive MBC patients progressing during positive MBC patients progressing during

trastuzumabtrastuzumab--based therapybased therapy

Pertuzumab + Pertuzumab + trastuzumabtrastuzumab

Cohorts Cohorts 1 and 21 and 2

HER2HER2--positive MBC positive MBC progressing on progressing on

15 patients received15 patients receivedpertuzumabpertuzumabPDPD

HER2HER2--positive MBC positive MBC progressing on trastuzumab progressing on trastuzumab

+ chemotherapy + chemotherapy (Cohort 1, n=24;(Cohort 1, n=24;Cohort 2, n=42)Cohort 2, n=42)

•• Primary objectivesPrimary objectives–– safety (evaluate safety of combined antibody treatment)safety (evaluate safety of combined antibody treatment)

–– efficacy (response rate + stabilization of disease = CBR)efficacy (response rate + stabilization of disease = CBR)

•• Heavily Heavily pretreatedpretreated populationpopulation–– median 3 prior lines of therapy in the metastatic settingmedian 3 prior lines of therapy in the metastatic setting

Baselga et al. J Clin Oncol 2010

progressing on progressing on trastuzumab + trastuzumab +

chemotherapy (n=29)chemotherapy (n=29)

pertuzumabpertuzumab+ +

trastuzumabtrastuzumabCohort 3Cohort 3

PertuzumabPertuzumabPDPD

PertuzumabPertuzumab / / trastuzumabtrastuzumab combination combination therapy more active than treatment with therapy more active than treatment with

either agent aloneeither agent alone

Cohorts 1 and 2Cohorts 1 and 2(P + T) (P + T) (n=66)(n=66)

Cohort 3 Cohort 3 (P)(P)

(n=27(n=27aa))

Cohort 3 Cohort 3 (P (P →→→→→→→→ P + T)P + T)

(n=11(n=11bb))

CR, %CR, % 7.67.6 0.00.0 0.00.0

PR, %PR, % 16.716.7 3.43.4 21.421.4

ORR, %ORR, % 24.224.2 3.43.4 21.421.4

SD SD >>6 months, %6 months, % 25.825.8 6.96.9 21.421.4

CBR, % CBR, % (CR + PR + SD (CR + PR + SD >>6 months)6 months) 50.050.0cc 10.310.3 37.537.5

PD, %PD, % 50.050.0 82.882.8 57.157.1

Baselga et al. J Clin Oncol 2010

CLEOPATRA: a Phase III trial of CLEOPATRA: a Phase III trial of trastuzumabtrastuzumab + + pertuzumabpertuzumab in the in the

1st1st--line settingline setting

1:1 1:1 HER2HER2--positivepositiveMBC (n=800MBC (n=800aa))

Docetaxel + trastuzumab + placeboDocetaxel + trastuzumab + placebo

Docetaxel + trastuzumab Docetaxel + trastuzumab + pertuzumab + pertuzumab

An international, Phase III, randomised, doubleAn international, Phase III, randomised, double--blind, blind, placeboplacebo--controlled study (~250 sites worldwide)controlled study (~250 sites worldwide)

•• End pointsEnd points

–– PFS and OSPFS and OS

–– quality of lifequality of life

–– biomarker analysisbiomarker analysis

Docetaxel + trastuzumab Docetaxel + trastuzumab + pertuzumab + pertuzumab

Baselga et al, N Engl J Med 2011

Cleopatra: Independently Cleopatra: Independently assessed PFSassessed PFS

n = 433 PFS eventsn = 433 PFS events

60

70

80

90

100 Ptz + T + D: median 18.5 months

Pla + T + D: median 12.4 months

free s

urviva

l (%

)

402 345 267 139 83 32 10 0 0Ptz + T + D

406 311 209 93 42 17 7 0 0Pla + T + D

Time (months)0 5 10 15 20 25 30 35 40

0

10

20

30

40

50

60

HR = 0.6295% CI 0.51‒0.75

p<0.0001

Prog

ress

ion-

free s

urviva

l (%

)

Stratified by prior treatment status and regionBaselga et al, N Engl J Med 2011

Exposure to study treatment in Exposure to study treatment in CleopatraCleopatra

PlaceboPlacebo+ + trastuzumabtrastuzumab+ + docetaxeldocetaxel((nn = 397)= 397)

PertuzumabPertuzumab+ + trastuzumabtrastuzumab+ + docetaxeldocetaxel((nn = 407)= 407)

Study treatmentStudy treatmentTime on any treatment (median), monthsTime on any treatment (median), months 11.811.8 18.118.1

Study treatmentStudy treatmentTime on any treatment (median), monthsTime on any treatment (median), months 11.811.8 18.118.1

DocetaxelDocetaxelDose intensity (median), mg/mDose intensity (median), mg/m22/week/weekNumber of cycles administered, median Number of cycles administered, median

(range)(range)

24.824.88 (18 (1‒‒41)41)

24.624.68 (18 (1‒‒35)35)

Baselga et al, N Engl J Med 2011

NeoSphereNeoSphere: study design: study design

THP (THP (nn=107)=107)docetaxeldocetaxel + + trastuzumabtrastuzumab ++pertuzumabpertuzumab

HP (n=107)HP (n=107)

SS

UU

RR

GG

FEC q3w x 3FEC q3w x 3trastuzumab q3w cycles 5trastuzumab q3w cycles 5––1717


TH (n=107)TH (n=107)docetaxel + docetaxel + trastuzumab trastuzumab

Patients with Patients with operable or operable or locally advanced locally advanced /inflammatory* /inflammatory* HER2HER2--positive positive BCBC

HP (n=107)HP (n=107)trastuzumab + trastuzumab + pertuzumab pertuzumab

TP (n=96)TP (n=96)docetaxel + docetaxel + pertuzumab pertuzumab

EE

RR

YY

docetaxel q3w x 4docetaxel q3w x 4→→FEC q3w x 3 FEC q3w x 3 trastuzumab q3w cycles 5trastuzumab q3w cycles 5––1717


Study dosing: q3w x 4Study dosing: q3w x 4

ChemoChemo--nanaïïve & ve & primary tumors primary tumors >2cm (>2cm (N=417)N=417)

BC, breast cancer; FEC, 5BC, breast cancer; FEC, 5--fluorouracil, fluorouracil, epirubicinepirubicin and and cyclophosphamidecyclophosphamide*Locally advanced=T2*Locally advanced=T2––3, N23, N2––3, M0 or T4a3, M0 or T4a––c, any N, M0; operable=T2c, any N, M0; operable=T2––3, N03, N0––1, M0; inflammatory = T4d, 1, M0; inflammatory = T4d, any N, M0any N, M0H, H, trastuzumabtrastuzumab; P, ; P, pertuzumabpertuzumab; T, ; T, docetaxeldocetaxel

Gianni L et al. SABCS 2010

NeoSphereNeoSphere pCRpCR rates: rates: ITTITT

P=0.0141P=0.01415050

4040

3030

95% C

I95% C

IP=0.0198P=0.0198

P=0.003P=0.003

45.845.83030

2020

1010

00THTH THPTHP HPHP TPTP

pCR

pCR, %

, % ±± ±± ±± ±±

95% C

I95% C

I

29.029.0

45.845.8

16.816.8

24.024.0


4040

5050

6060

7070

ER or PR posER or PR posER and PR negER and PR neg

pCRpCR and hormone receptors and hormone receptors statusstatus

63.263.2

95% C

I95% C

I

00

1010

2020

3030

4040

THTH THPTHP HPHP TPTP

20.020.0

26.026.0

17.417.4

36.836.8

29.129.1 30.030.0

5.95.9

pCR

pCR, %

, % ±± ±± ±± ±±

95% C

I95% C

I


Heavily pretreated patients Heavily pretreated patients with HER2with HER2--positive positive

metastatic breast cancer metastatic breast cancer

Lapatinib 1500 mg PO QDLapatinib 1500 mg PO QD(n = 148)(n = 148)

Optional crossover to Optional crossover to trastuzumab arm if trastuzumab arm if

PD after 4 wks (n = 77)PD after 4 wks (n = 77)

Updated Analysis: Phase III Trial of Updated Analysis: Phase III Trial of LapatinibLapatinib ±± TrastuzumabTrastuzumab in HER2+ MBC. in HER2+ MBC.

Primary endpoint:Primary endpoint:PFSPFS

Secondary endpoints:Secondary endpoints:metastatic breast cancer metastatic breast cancer

and progression on and progression on trastuzumabtrastuzumab

(N = 296)(N = 296)

Stratified by visceral disease Stratified by visceral disease and hormone receptor statusand hormone receptor status

Lapatinib 1000 mg PO QD +Lapatinib 1000 mg PO QD +Trastuzumab 4 mg/kg loading Trastuzumab 4 mg/kg loading dose, then 2 mg/kg IV wklydose, then 2 mg/kg IV wkly

(n = 148)(n = 148)

PD after 4 wks (n = 77)PD after 4 wks (n = 77) Secondary endpoints:Secondary endpoints:OSOSORRORRCBRCBR

Blackwell K, et al. J Clin Oncol 2010

ProgressionProgression--Free Survival in ITTFree Survival in ITT

L L N = 145N = 145

L+T L+T N = 146N = 146

Progressed or Died, NProgressed or Died, N 128128 127127

Median, weeksMedian, weeks 8.18.1 12.012.0

Hazard ratio (95% CI)Hazard ratio (95% CI) 0.73 (0.57, 0.93)0.73 (0.57, 0.93)

LogLog--rank P rank P valuevalue .008.008

Cum

ulative

% A

live

withou

t Pr

ogre

ssion

Cum

ulative

% A

live

withou

t Pr

ogre

ssion

28%28%4040

6060

8080

100100

6 Month PFS6 Month PFS

Cum

ulative

% A

live

withou

t Pr

ogre

ssion

Cum

ulative

% A

live

withou

t Pr

ogre

ssion

Patients At RiskPatients At Risk

148148148148

LLL+TL+T

53537373

21214242

13132727

5588

0022

13%13%

28%28%

00

2020

4040

00 1010 2020 3030 4040 5050 6060Time from Randomization (weeks)Time from Randomization (weeks)

Blackwell K et al. J Clin Oncol 2010

Updated Overall Survival in ITTUpdated Overall Survival in ITT

L L N =145N =145

L+T L+T N =146N =146

Died, N (%)Died, N (%) 113 (78)113 (78) 105 (72)105 (72)

Median, monthsMedian, months 9.59.5 1414

Hazard ratio (95% CI)Hazard ratio (95% CI) 0.74 (0.57, 0.97)0.74 (0.57, 0.97)

LogLog--rank P rank P valuevalue .026.026

6 Month 6 Month OSOS

80%80%

70%70% 56%56%



41%41%

Blackwell K et al. J Clin Oncol 2010

NeoNeo--ALTTO trial (BIG 01ALTTO trial (BIG 01--06)06)

Invasive operableInvasive operableHER2+ BCHER2+ BCT > 2 cm T > 2 cm (IBC excluded)(IBC excluded)LVEF LVEF ≥≥≥≥≥≥≥≥ 50%50%

lapatiniblapatinib

trastuzumabtrastuzumab

FFEEC C

SSUURR

RRAANNDD

lapatinib lapatinib


paclitaxel paclitaxel


Stratification:Stratification:•• T≤5 cm vs. T>5 cmT≤5 cm vs. T>5 cm•• ER or ER or PgRPgR + vs. + vs.

ER & ER & PgRPgR ––•• N 0N 0--1 vs. N 1 vs. N ≥ 2≥ 2•• BCS or notBCS or not

LVEF LVEF ≥≥≥≥≥≥≥≥ 50%50%N=450 N=450

34 weeks34 weeks

52 weeks of anti52 weeks of anti--HER2 therapyHER2 therapy


lapatiniblapatinibtrastuzumabtrastuzumab

C C

XX

33

RRGGEERRYY

DDOOMMIIZZEE

lapatiniblapatinibtrastuzumabtrastuzumab


paclitaxelpaclitaxel

+ 12 wks+ 12 wks6 wks6 wks

Baselga J et al. SABCS 2010

Efficacy Efficacy –– pCRpCR and and tpCRtpCR


pCRpCR by Hormone Receptor Statusby Hormone Receptor Status


TrastuzumabTrastuzumab plus plus BevacizumabBevacizumab: : synergy in a breast cancer synergy in a breast cancer

xenograftxenograft modelmodel

Mean

tumou

r vo

lume

Mean

tumou

r vo

lume

SEM

SEM

650650600600550550500500450450400400350350

ControlControl

TrastuzumabTrastuzumab (30/15mg/kg every week (30/15mg/kg every week i.pi.p.).)

BevacizumabBevacizumab (5mg/kg every 2 weeks (5mg/kg every 2 weeks i.pi.p.).)

BevacizumabBevacizumab + + TrastuzumabTrastuzumab

TrastuzumabTrastuzumab + + BevacizumabBevacizumab

Scheuer W et al. EORTC-NCI-AACR 2006

SEM = standard error of meanSEM = standard error of mean

Treatment period (days)Treatment period (days)

Mean

tumou

r vo

lume

Mean

tumou

r vo

lume

(mm

(mm

33) ) ±± ±± ±± ±±

SEM

SEM

350350300300250250200200150150100100505000

00 1010 2020 3030 4040 5050 6060 7070 8080

TrastuzumabTrastuzumab + + BevacizumabBevacizumab

•• AEsAEs

–– one grade 4 one grade 4 LVEF declineLVEF decline

–– seven grade 3 seven grade 3

Patient

s (%

)Pa

tient

s (%

)

5151

6060

5050

4040

Phase II trial of Phase II trial of TrastuzumabTrastuzumab with with BevacizumabBevacizumab in firstin first--line MBCline MBC

ORR 54%ORR 54%

–– seven grade 3 seven grade 3 hypertensionhypertension

–– one grade 3 one grade 3 proteinuriaproteinuria

–– one grade 3 one grade 3 dyspnoeadyspnoea

Patient

s (%

)Pa

tient

s (%

)

33

3030

1616

Clinical response (n=37)Clinical response (n=37)

Pegram M et al. Semin Oncol 2006

4040

3030

2020

1010

00

CRCR PRPR SDSD PDPD

AVEREL AVEREL Study schemaStudy schema

Previously untreated Previously untreated HER2HER2--positive LR/mBCpositive LR/mBC

•• Centrally confirmed IHC 3+ or Centrally confirmed IHC 3+ or IHC 2+ and FISH/CISH+IHC 2+ and FISH/CISH+

•• Measurable or evaluable Measurable or evaluable diseasedisease

•• ECOG PS 0/1ECOG PS 0/1No CNS metastasesNo CNS metastases

H: 8H: 8→→6 mg/kg6 mg/kgDOC: 100 mg/mDOC: 100 mg/m22

both q3wboth q3w

H: 8H: 8→→6 mg/kg6 mg/kgDOC: 100 mg/mDOC: 100 mg/m22

BEV: 15 mg/kg BEV: 15 mg/kg

RR

•• ECOG PS 0/1ECOG PS 0/1•• No CNS metastasesNo CNS metastases

DOC: 100 mg/mDOC: 100 mg/mBEV: 15 mg/kg BEV: 15 mg/kg

all q3wall q3wStratification variablesStratification variables•• Prior (neo)adjuvant Prior (neo)adjuvant taxanetaxane (yes (yes vsvs no no

[no chemotherapy/relapse <12 months [no chemotherapy/relapse <12 months vsvs ≥12 months since last ≥12 months since last chemotherapy])chemotherapy])

•• Adjuvant H (yes Adjuvant H (yes vsvs no)no)

•• ER/ER/PgRPgR status (positive status (positive vsvs negative)negative)

•• Measurable disease (yes Measurable disease (yes vsvs no)no)

•• H and BEV continued to PD or H and BEV continued to PD or unacceptable toxicityunacceptable toxicity

•• DOC given until PD or unacceptable DOC given until PD or unacceptable toxicity (planned minimum of 6 toxicity (planned minimum of 6 cycles)cycles)


IRCIRC--assessed PFS assessed PFS Est

imate

d p

robability

Est

imate

d p

robability

1.01.0

0.80.8

0.60.6

H + DOCH + DOC(n=208)(n=208)

H + DOC + BEVH + DOC + BEV(n=216)(n=216)

Events, n (%)Events, n (%) 114 (54.8)114 (54.8) 111 (51.4)111 (51.4)

Median PFS, monthsMedian PFS, months(95% CI)(95% CI)

13.913.9(11.2(11.2‒‒16.7)16.7)

16.816.8(14.1(14.1‒‒19.5)19.5)

HR, unstratifiedHR, unstratified(95% CI)(95% CI)

0.760.76

(0.59(0.59‒‒0.99)0.99)

LogLog--rank prank p--valuevalue 0.04140.0414

HR, stratifiedHR, stratifiedaa

(95% CI)(95% CI)0.72 0.72

(0.54(0.54‒‒0.94)0.94)

Est

imate

d p

robability

Est

imate

d p

robability

Time (months)Time (months)00 66 1212 1818 2424 3030 3636 4242 4848 5454

0.40.4

0.20.2

0.0 0.0

No. at risk:No. at risk:208208 149149 7575 3939 2424 1414 77 22 11 00216216 173173 101101 5858 3232 1515 1010 77 22 00

13.913.9 16.816.8

LogLog--rank rank pp--valuevalue 0.01620.0162


1.01.0

0.80.8

AVEREL AVEREL PFS according to baseline PFS according to baseline plasma plasma VEGFVEGF--AA

PlasmaPlasmaVEGFVEGF--AA HRHR (95% CI)(95% CI)

≤ median≤ median 0.830.83 (0.50(0.50‒‒1.36)1.36)

> median> median 0.700.70 (0.43(0.43‒‒1.14)1.14)

H + DOC + H + DOC + BEV betterBEV better

H + DOC H + DOC betterbetter

Est

imate

d p

robability

Est

imate

d p

robability

H + DOC low VEGFH + DOC low VEGF--A (A (nn=45)=45)

H + DOC high VEGFH + DOC high VEGF--A (n=37)A (n=37)

H + DOC + BEV low VEGFH + DOC + BEV low VEGF--A (A (nn=36)=36)

H + DOC + BEV high VEGFH + DOC + BEV high VEGF--A (A (nn=43)=43)

0.60.6

0.40.4

0.20.2

0.00.000 66 1212 1818 2424 3030 3636 4242 4848 5454

0.20.2 0.50.5 11 22 55HRHR

Est

imate

d p

robability

Est

imate

d p

robability

Time (months)Time (months)

13.613.68.58.5 16.516.516.616.6


pCRpCR and clinical response rates by and clinical response rates by neoadjuvantneoadjuvant systemic therapy typesystemic therapy type

PHPH--FECH FECH

(N=235)(N=235)

TCH TCH

(N=65)(N=65)

NN PercentPercent NN PercentPercent PP

pCRpCR

No pCRNo pCR 8989 39.439.4 3434 56.756.7 0.0160.0167070 P=0.016P=0.016

No pCRNo pCR 8989 39.439.4 3434 56.756.7 0.0160.016

pCRpCR 137137 60.660.6 2626 43.343.3

ClinClin ResponseResponse

CRCR 172172 80.880.8 3333 58.958.9 0.0060.006

PRPR 1515 7.07.0 1111 19.619.6

SDSD 1616 7.57.5 1111 19.619.6

PDPD 1010 4.74.7 11 1.81.8

RadRad ResponseResponse

CRCR 9696 41.241.2 1515 28.828.8 0.210.21

PRPR 130130 55.855.8 3636 69.269.2

SDSD 77 3.03.0 11 1.91.9

00

1010

2020

3030

4040

5050

6060

PHPH--FECH FECH TCHTCH

60.6%60.6% 43.3%43.3%

Bayraktar S et al. Cancer 2011

Multivariate logistic regression Multivariate logistic regression model for model for pCRpCR

pCRpCR

OROR 95% CI 95% CI PP

PHPH--FECH FECH vs.vs. TCHTCH 1.451.45 1.06 1.06 -- 1.981.98 0.020.02

Age: >50 Age: >50 vs.vs. ≤50≤50 1.141.14 0.68 0.68 -- 1.911.91 0.610.61

Race: Black Race: Black vs.vs. NonNon--BlackBlack 0.690.69 0.34 0.34 -- 1.41.4 0.300.30Race: Black Race: Black vs.vs. NonNon--BlackBlack 0.690.69 0.34 0.34 -- 1.41.4 0.300.30

BMIBMI: Overweight/obese : Overweight/obese vsvs. . Normal/underweightNormal/underweight

1.221.22 0.69 0.69 -- 2.142.14 0.490.49

ER Status: positive ER Status: positive vs.vs. Negative/weakNegative/weak 0.320.32 0.19 0.19 -- 0.550.55 <0.001<0.001

Grade: III Grade: III vs.vs. I/III/II 1.811.81 1.00 1.00 -- 3.273.27 0.050.05

Clinical T: T4 Clinical T: T4 vs.vs. T1T1--33 0.520.52 0.27 0.27 -- 0.980.98 0.0430.043

ClinicalClinical N: N1N: N1--3 3 vs.vs. N0N0 1.111.11 0.62 0.62 -- 1.991.99 0.730.73


RFS by NST type RFS by NST type

All PatientsAll Patients No IBC PatientsNo IBC Patients


PromisesPromises

•• TT--DM1 and its developmentDM1 and its development

•• subsub--groups of HER2groups of HER2--positive cancerspositive cancers

•• Targeting mechanisms of resistanceTargeting mechanisms of resistance

•• AntiAnti--HER2 vaccinesHER2 vaccines•• AntiAnti--HER2 vaccinesHER2 vaccines

Numerous treatments for HER2Numerous treatments for HER2--positive breast cancer in developmentpositive breast cancer in development

•• HER2 HER2 dimerizationdimerization inhibitorinhibitor

•• HER2 ADCHER2 ADC

•• PI3K pathway inhibitorsPI3K pathway inhibitors

•• EGFR/HER2 Tyrosine EGFR/HER2 Tyrosine kinasekinase inhibitorsinhibitors

•• HSP 90 inhibitorsHSP 90 inhibitors•• HSP 90 inhibitorsHSP 90 inhibitors

•• VEGF receptor inhibitorsVEGF receptor inhibitors

•• HER3 Monoclonal antibodiesHER3 Monoclonal antibodies

•• IGF1R Monoclonal antibodies and IGF1R Monoclonal antibodies and TKIsTKIs

•• IGF1R/IR Tyrosine IGF1R/IR Tyrosine kinasekinase inhibitorsinhibitors

•• cMET Monoclonal antibodies and cMET Monoclonal antibodies and TKIsTKIs

•• Anti HER2 vaccinesAnti HER2 vaccines

Monoclonal antibody: trastuzumabMonoclonal antibody: trastuzumab

Target expression: HER2Target expression: HER2

Cytotoxic agent: DM1Cytotoxic agent: DM1

TT--DM1: 1stDM1: 1st--inin--class HER2 antibodyclass HER2 antibody--drug drug conjugate (ADC)conjugate (ADC)

Highly potent chemotherapyHighly potent chemotherapy(maytansine derivative)(maytansine derivative)

Cytotoxic agent: DM1Cytotoxic agent: DM1

Systemically stableSystemically stableBreaks down in target cancer cellBreaks down in target cancer cell

LinkerLinkerTT--DM1DM1

TT--DM1 selectively delivers DM1 to DM1 selectively delivers DM1 to HER2HER2--positive tumor cellspositive tumor cells

TT--DM1 binds to the HER2 DM1 binds to the HER2 protein on cancer cellsprotein on cancer cells

•• Targeted intracellular delivery of a potent Targeted intracellular delivery of a potent antimicrotubule agent, DM1antimicrotubule agent, DM1

•• Spares normal tissue from toxicity of free DM1Spares normal tissue from toxicity of free DM1

•• TrastuzumabTrastuzumab--like activity by binding to HER2like activity by binding to HER2HER2HER2

ReceptorReceptor--TT--DM1 complex is DM1 complex is internalized into HER2internalized into HER2--positive cancer cellpositive cancer cell

Potent antimicrotubule Potent antimicrotubule agent is released once agent is released once inside the HER2inside the HER2--positivepositivetumor celltumor cell

Phase II trial of TPhase II trial of T--DM1 in HER2DM1 in HER2--positive MBC positive MBC patients progressing during HER2patients progressing during HER2--targeted therapytargeted therapy

TT--DM1DM13.6 mg/kg q3w3.6 mg/kg q3w

Patients with HER2Patients with HER2--positive MBC (n=110)positive MBC (n=110)Prior exposure to Prior exposure to anthracyclineanthracycline, , taxanetaxane, , capecitabinecapecitabine, ,

lapatiniblapatinib and and trastuzumabtrastuzumabPD on last regimen receivedPD on last regimen received

Tumour responseTumour response

Independent Independent reviewreview(n=110)(n=110)

Investigator Investigator assessedassessed(n=110)(n=110)

ORR, %ORR, %(95% CI)(95% CI)

32.732.7(24.1, 42.1)(24.1, 42.1)

30.030.0(22.0, 39.4)(22.0, 39.4)

Krop et al. SABCS 2009IRF, independent review facility

(95% CI)(95% CI) (24.1, 42.1)(24.1, 42.1) (22.0, 39.4)(22.0, 39.4)

CRCR 00 1.81.8

PRPR 32.732.7 28.228.2

SDSDaa 46.446.4 52.752.7

PDPD 18.218.2 13.613.6

UnevaluableUnevaluable 1.81.8 0.90.9

MissingMissing 0.90.9 2.72.7

CBR, %CBR, %(95% CI)(95% CI)

44.544.5(35.1, 54.3)(35.1, 54.3)

40.040.0(31.1, 49.3)(31.1, 49.3)

Median PFS, months (range)Median PFS, months (range) 7.3 (07.3 (0--11.7)11.7) n/an/a

Phase II Study Phase II Study DesignDesign

1:1 1:1 HER2HER2--positive, positive, recurrent locally recurrent locally advanced breast advanced breast cancer or MBC cancer or MBC

(N=137)(N=137)

TT--DM1DM13.6 mg/kg q3w IV3.6 mg/kg q3w IV

(n=67)(n=67)

TrastuzumabTrastuzumab8 8 mg/kg loading dose; mg/kg loading dose;

6 mg/kg q3w IV6 mg/kg q3w IV+ + DocetaxelDocetaxel

Crossover toCrossover toTT--DM1 DM1 (optional)(optional)

PDPD

PDPD

•• Randomized, phase II, international, openRandomized, phase II, international, open--label studylabel study

•• Stratification factors: World region, prior adjuvant trastuzumab therapy, diseaseStratification factors: World region, prior adjuvant trastuzumab therapy, disease--free interval free interval

•• Primary end points: PFS by investigator assessment, and safetyPrimary end points: PFS by investigator assessment, and safety

•• Data analyses were based on clinical data cut of Nov 15, 2010 prior to TData analyses were based on clinical data cut of Nov 15, 2010 prior to T--DM1 DM1 crossovercrossover

•• Key secondary end points: OS, ORR, DOR, CBR, and QOLKey secondary end points: OS, ORR, DOR, CBR, and QOL

+ + DocetaxelDocetaxel7575 or 100or 100 mg/mmg/m22 q3wq3w

(n=70)(n=70)

(optional)(optional)

Hurvitz et al, SABCS 2011

Objective Response by Investigator Objective Response by Investigator

Patients Patients With Measurable Disease at BaselineWith Measurable Disease at Baseline

TrastuzumabTrastuzumab + + docetaxeldocetaxel(n=69)(n=69)

TT--DM1 DM1 (n=67)(n=67)

Patients with an objective response, n (%)Patients with an objective response, n (%) 40 (58.0)40 (58.0) 43 (64.2)43 (64.2)

95% CI 95% CI 45.545.5––69.269.2 51.851.8––74.874.8

Patients with clinical benefit,Patients with clinical benefit, n (%)n (%) 56 (81.2)56 (81.2) 50 (74.6)50 (74.6)

95% CI95% CI 70.770.7––89.189.1 63.263.2––84.2 84.2 95% CI95% CI 70.770.7––89.189.1 63.263.2––84.2 84.2

Objective responses, n (%)Objective responses, n (%)

Complete responseComplete response 3 (4.3)3 (4.3) 7 (10.4)7 (10.4)

Partial responsePartial response 37 (53.6)37 (53.6) 36 (53.7)36 (53.7)

Stable diseaseStable disease 23 (33.3)23 (33.3) 13 (19.4)13 (19.4)

Progressive diseaseProgressive disease 4 (5.8)4 (5.8) 8 (11.9)8 (11.9)

Unable to evaluate or missingUnable to evaluate or missing 2 (2.9)2 (2.9) 3 (4.5)3 (4.5)

Median duration of response, Median duration of response, mosmos 9.59.5 NRNR

95% CI95% CI 6.66.6––10.610.6 ——


ProgressionProgression--Free Survival Free Survival by by InvestigatorInvestigator

Randomized PatientsRandomized Patients

Prop

ortion

pro

gress

ion

Prop

ortion

pro

gress

ion--

free

free

1.01.0

0.80.8

0.60.6

MedianMedianPFS, PFS, mosmos

Hazard Hazard ratioratio 95% CI95% CI

LogLog--rank rank PPvaluevalue

9.29.2

14.214.2 0.5940.594 0.3640.364––0.9680.968 0.03530.0353

TrastuzumabTrastuzumab+ + docetaxeldocetaxel (n=70)(n=70)

TT--DM1 DM1 (n=67)(n=67)

Time (months)Time (months)

Prop

ortion

pro

gress

ion

Prop

ortion

pro

gress

ion

0.40.4

0.20.2

0.00.000 22 44 66 88 1010 1212 1414 1616 1818 2020



HER2HER2--positive incurable locally advanced positive incurable locally advanced breast cancer or MBC breast cancer or MBC

Prior trastuzumab and / or taxanePrior trastuzumab and / or taxane(n=580)(n=580)

EMILIA: ongoing Phase III study of TEMILIA: ongoing Phase III study of T--DM1 DM1 vsvs capecitabinecapecitabine + + lapatiniblapatinib in the in the

2nd2nd--line settingline settingPrimary end pointsPrimary end points•• PFS (independent PFS (independent

assessment)assessment)

•• SafetySafety

Secondary end Secondary end pointspoints

(n=580)(n=580)pointspoints

•• OSOS

•• PFS (investigator PFS (investigator assessment)assessment)

•• ORRORR

•• CBR CBR

•• DoRDoR

•• Quality of lifeQuality of life

•• TTFTTF

TT--DM1 DM1 3.6 mg/kg q3w3.6 mg/kg q3w

Capecitabine Capecitabine + lapatinib+ lapatinib

1:1 1:1

www.clinicaltrials.gov

PI3K pathway: markers vs. targetsPI3K pathway: markers vs. targets

INPP4BLKB1

Modified from McAuliffe P et al. Clin Breast Cancer 2010

LKB1

Phase I Study of Phase I Study of EverolimusEverolimus Plus Weekly Plus Weekly PaclitaxelPaclitaxel and and TrastuzumabTrastuzumab in Patients With in Patients With Metastatic Breast Cancer Pretreated With Metastatic Breast Cancer Pretreated With

TrastuzumabTrastuzumab

Andre F et al, J Clin Oncol 2010

Phase I/II Study of Phase I/II Study of TrastuzumabTrastuzumab in Combinationin CombinationWith With EverolimusEverolimus (RAD001) in Patients With(RAD001) in Patients With

HER2HER2--Overexpressing Metastatic Breast Cancer WhoOverexpressing Metastatic Breast Cancer WhoProgressed on Progressed on TrastuzumabTrastuzumab--Based TherapyBased Therapy

Morrow PK et al, J Clin Oncol 2011

EverolimusEverolimus in HER2in HER2--positive positive MBCMBC

BOLERO 1BOLERO 1


BOLERO 3BOLERO 3

HER2HER2--Derived Peptide VaccineDerived Peptide Vaccine

•• E75E75–– 9 9 aaaa peptide from extracellular domainpeptide from extracellular domain

–– ImmunodominantImmunodominant epitopeepitope of HER2/of HER2/neuneu

–– MHC class I peptide MHC class I peptide →→ stimulated CD8stimulated CD8++–– MHC class I peptide MHC class I peptide →→ stimulated CD8stimulated CD8++

T cellsT cells

–– High affinity for HLAHigh affinity for HLA--A2 /A3A2 /A3

E75E75GMGM--CSFCSF

HER2/HER2/neuneu

Clinical Benefit to Clinical Benefit to VaccinationVaccination

0.040.0414.2%14.2%5.6%5.6%Recurrence Recurrence

PP--valuevalueControlControlVaccinatedVaccinated

DFSDFS

Primary analysis at 18 months median followPrimary analysis at 18 months median follow--upup

0.100.1095.1%95.1%99.0%99.0%Overall Overall SurvivalSurvival

0.040.0477.0%77.0%92.5%92.5%Disease Disease Free Free SurvivalSurvival

0.040.0414.2%14.2%5.6%5.6%Recurrence Recurrence RateRate

p=0.04p=0.04

Peoples et al. Clin Cancer Res 2008

AE37/GP2 Phase II TrialAE37/GP2 Phase II Trial

SSTTRRAATTIIFFYY

RRAANNDDOOMMIIZZEE

AE37+GMAE37+GM

GM onlyGM only

Specific AimsSpecific Aims

1.1. RecurrenceRecurrence2.2. Time to Time to

RecurrenceRecurrence3.3. Immunologic Immunologic

A2A2--•• NP or highNP or high--risk NNrisk NN

•• HER2 IHC HER2 IHC 1+, 2+ or 3+1+, 2+ or 3+ GM onlyGM only 3.3. Immunologic Immunologic

response response correlationcorrelation

SSTTRRAATTIIFFYY

RRAANNDDOOMMIIZZEE

GM onlyGM only

GP2+GMGP2+GM

A2+A2+

1+, 2+ or 3+1+, 2+ or 3+•• NED after NED after

SOC therapySOC therapy


ConclusionsConclusions

•• Much progress and many promisesMuch progress and many promises

•• HER2 is still a therapeutic target even in HER2 is still a therapeutic target even in trastuzumabtrastuzumab resistanceresistance

•• Don’t automatically abandon Don’t automatically abandon trastuzumabtrastuzumab after the onset of after the onset of resistanceresistance

•• Combined receptor inhibitors or receptor inhibitors combined with Combined receptor inhibitors or receptor inhibitors combined with downstream/alternative signaling inhibitors show better results downstream/alternative signaling inhibitors show better results and will become standardand will become standard

•• De Novo and acquired resistance occur and there are many De Novo and acquired resistance occur and there are many potential mechanisms. potential mechanisms.

•• Predicting the mechanism of resistance in the primary tumor will Predicting the mechanism of resistance in the primary tumor will be critical for appropriate patient selection and saving costsbe critical for appropriate patient selection and saving costs

Thank you !!!!Thank you !!!!

[email protected]@mdanderson.org

Thanks to Luca Gianni for providing all slide materialsThanks to Luca Gianni for providing all slide materials

ana maria gonzalezana maria gonzalez--angulo, …ana maria gonzalezana maria gonzalez--angulo, m.d....

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