Trastuzumab en Cancer de Mama - Medwave · Trastuzumab en Cancer de Mama Ana Maria GonzalezAna...

Trastuzumab en Trastuzumab en Cancer de MamaCancer de Mama

Ana Maria GonzalezAna Maria Gonzalez--Angulo, M.D.Angulo, M.D.Assistant Professor of MedicineAssistant Professor of Medicine

Department of Breast Medical OncologyDepartment of Breast Medical OncologyDepartment of Systems BiologyDepartment of Systems Biology

HER2 Pathway BiologyHER2 Pathway Biology

Meric-Bernstam and Hung, Clin Can Res, 2006

Trastuzumab:Trastuzumab:Humanized AntiHumanized Anti--HER2 MAbHER2 MAb

•• Targets HER2 proteinTargets HER2 protein

•• High affinity (KHigh affinity (Kdd=0.1 =0.1 nM) and specificitynM) and specificity

HER2 epitopes recognized by hypervariable murine antibody fragment

•• 95% human, 5% 95% human, 5% murinemurine•• Decreases potential Decreases potential

for immunogenicityfor immunogenicity•• Increases potential for Increases potential for

recruiting immune recruiting immune effector mechanismseffector mechanisms

Human IgG-1

Normal breast epitheliumNormal breast epithelium HER2HER2--positive tumor cell positive tumor cell

Defining HER2Defining HER2--Positive StatusPositive Status

•• Overexpression:Overexpression: an abnormal increase in the an abnormal increase in the number of HER2 protein receptors on the cell surface number of HER2 protein receptors on the cell surface

•• Amplification:Amplification: an abnormal increase in the number an abnormal increase in the number of HER2 gene copies in the cell nucleusof HER2 gene copies in the cell nucleus

Normal breast epitheliumNormal breast epithelium(~20,000 receptor molecules)(~20,000 receptor molecules)

HER2HER2--positive tumor cell positive tumor cell (Up to (Up to ∼∼∼∼∼∼∼∼11--2 million receptor molecules)2 million receptor molecules)

Courtesy of Jeffrey Ross, Albany Medical College, Albany, NY.

IHC Detection of HER2 ProteinIHC Detection of HER2 Protein

Courtesy of Jeffrey Ross, Albany Medical College, Albany, NY.

2+

Normal tissue (cytoplasmic)

1+

3+

HER2 Diagnostics: Fluorescence HER2 Diagnostics: Fluorescence In In SituSitu HybridizationHybridization

HER2HER2//CEP 17CEP 17: 10 (+): 10 (+)HER2HER2//CEP 17CEP 17: 2.0 (: 2.0 (--))

Adjuvant Trastuzumab for Early Adjuvant Trastuzumab for Early HER2HER2--positive Breast Cancerpositive Breast Cancer

NSABP BNSABP B--3131

NCCTG N9831NCCTG N9831

Arm 1Arm 1Arm 2Arm 2

Arm AArm A

Arm BArm B

Arm CArm C

= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4

= paclitaxel (T) 175 mg/m2 q 3 wk x 4= paclitaxel (T) 175 mg/m2 q 3 wk x 4

= paclitaxel (T) 80 mg/m2/wk x 12= paclitaxel (T) 80 mg/m2/wk x 12

= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

Romond EH, ASCO 2005

Arm 1Arm 1

Arm AArm A

Control: ACControl: AC→→→→→→→→T (n=1679)T (n=1679)

Investigational: ACInvestigational: AC→→→→→→→→T+H (1672)T+H (1672)

Arm BArm B

Arm CArm C

= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4= doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4

= paclitaxel (T) 175 mg/m2 q 3 wk x 4= paclitaxel (T) 175 mg/m2 q 3 wk x 4

= paclitaxel (T) 80 mg/m2/wk x 12= paclitaxel (T) 80 mg/m2/wk x 12

= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51= trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

Arm 2Arm 2


Patient and Tumor Characteristics (%)Patient and Tumor Characteristics (%)AC AC �� PaclitaxelPaclitaxel AC AC �� PaclitaxelPaclitaxel

+ Trastuzumab+ Trastuzumab

BB--31 31 N=872N=872

N9831N9831N=807N=807

BB--3131N=864N=864

N9831N9831N=808N=808

AgeAge

<50<50 5252 5151 5151 5050

5050--5959 3434 3434 3232 3232

≥60≥60 1515 1515 1616 1818

No. Pos NodesNo. Pos NodesNo. Pos NodesNo. Pos Nodes

00 00 1313 00 1111

11--33 5757 4848 5757 5050

44--99 2929 2525 2929 2525

10+ 1414 1515 1414 1414

Hormone Receptors

ER+ER+ 5353 5252 5151 5151

ER−ER− 4747 4646 4848 4848

PR+PR+ 4141 4141 3939 3939

PR−PR− 5858 5757 6060 6060

Romond et al. N Engl J Med 2005 Oct 20;353(16):1673-84.

Patient and Tumor Characteristics (%)Patient and Tumor Characteristics (%)

AC AC �� PaclitaxelPaclitaxel AC AC �� PaclitaxelPaclitaxel+ Trastuzumab+ Trastuzumab

BB--3131N=872N=872

N9831N9831N=807N=807

BB--3131N=864N=864

N9831N9831N= 808N= 808

Tumor SizeTumor Size

≤2.0 cm.≤2.0 cm. 4141 4040 3737 3838

2.12.1-- 4.0 cm.4.0 cm. 4343 4646 4444 47472.12.1-- 4.0 cm.4.0 cm. 4343 4646 4444 4747

>4.0 cm.>4.0 cm. 1414 1313 1717 1414

SurgerySurgery

Breast Conserv.Breast Conserv. 3838 3737 3838 3636

MastectomyMastectomy 6161 6161 6161 6363

Paclitaxel SchedulePaclitaxel Schedule

Q 3 weekQ 3 week 9292 00 9393 00

WeeklyWeekly 88 100100 77 100100


Joint Analysis: DiseaseJoint Analysis: Disease--Free SurvivalFree Survival

87%87%85%85%

75%75%%%

ACAC��TH TH �� HH

ACAC��TT

67%67%

NN EventsEventsACAC��TT 16791679 261261ACAC��THTH 16721672 134134

HR=0.48, 2P=3x10HR=0.48, 2P=3x10--1212

Years From RandomizationYears From Randomization


Joint Analysis: Overall SurvivalJoint Analysis: Overall Survival

ACAC��TH TH �� HH94%94%

91%91%

87%87%

92%92%ACAC��TT

NN DeathsDeathsACAC��TT 16791679 9292ACAC��THTH 16721672 6262

HR=0.67, 2P=0.015HR=0.67, 2P=0.015

Years From RandomizationYears From Randomization


Time to First Distant RecurrenceTime to First Distant Recurrence

80

90

100ACAC��THTH

AC��T

90%90% 90%90%

81%%

HR=0.47, 2P=8x10HR=0.47, 2P=8x10--1010

0 1 2 3 4 5

50

60

70 74%

NN EventsEventsACAC��TT 16791679 194194ACAC��THTH 16721672 9696


Joint Analysis: DiseaseJoint Analysis: Disease--Free SurvivalFree Survival

TumorTumorSizeSize

HormoneHormoneReceptorReceptor

AgeAge

≥≥ 4.1cm4.1cm2.12.1-- 4.0 cm4.0 cm

PositivePositiveNegativeNegative

≥≥60605050--59594040--4949≤39≤39

ALL DATAALL DATA

Hazard RatioHazard Ratio0.2 0.4 0.6 0.8 1.0 1.2 1.4

ProtocolProtocol

No.No.PositivePositiveNodesNodes

TumorTumorSizeSize

N9831N9831NSABP BNSABP B--3131

≥≥ 4.1cm4.1cm2.12.1-- 4.0 cm4.0 cm<2.0 cm<2.0 cm

10+10+44--9911--3300


NCCTG N9831 SchemaNCCTG N9831 Schema

RRAANNDDOOMM

Paclitaxel qw x 12Paclitaxel qw x 12Arm A:Arm A: AC q3w x 4AC q3w x 4

Paclitaxel qw x 12Paclitaxel qw x 12Arm B: Arm B: AC q3w x 4AC q3w x 4 H qw x 52H qw x 52OOMMIIZZEE

Radiation and/or hormonal therapy as indicatedRadiation and/or hormonal therapy as indicated

Paclitaxel qw x 12Paclitaxel qw x 12Arm B: Arm B: AC q3w x 4AC q3w x 4 H qw x 52H qw x 52

AC q3w x 4AC q3w x 4Paclitaxel qw x 12 Paclitaxel qw x 12

++H qw x 12H qw x 12

Arm C:Arm C: H qw x 40H qw x 40

DiseaseDisease--Free Survival: B vs CFree Survival: B vs CN9831N9831

100

90

80

70

60

AC AC →→ T T →→ HHEvents=84Events=84

AC AC →→ T + H T + H →→ HHEvents=53Events=53

60

50

40

30

20

10

00 1 2 3 4

Number of patients followedNumber of patients followedBB 842842 501501 285285 162162 2020CC 840840 520520 285285 178178 1717

%

Hazard ratio=0.64Hazard ratio=0.64Stratified logrank Stratified logrank 2P2P=0.0114=0.0114

HERAHERAWomen with Her2/neuWomen with Her2/neu--positive early breast cancerpositive early breast cancer

Histology Centrally ConfirmedHistology Centrally Confirmed

Surgery, (neo) Adjuvant Chemotherapy +/Surgery, (neo) Adjuvant Chemotherapy +/-- RadiotherapyRadiotherapy

StratificationStratificationStratificationStratificationAge, Nodes, Chemotherapy, Hormone receptors, Hormonal therapy, RegionAge, Nodes, Chemotherapy, Hormone receptors, Hormonal therapy, Region

RANDOMIZATIONRANDOMIZATION

TrastuzumabTrastuzumab8mg/kg8mg/kg→→→→→→→→6mg/kg6mg/kg

For 2 yearsFor 2 yearsn=1694n=1694

TrastuzumabTrastuzumab8mg/kg8mg/kg→→→→→→→→6mg/kg6mg/kg

For 1 yearsFor 1 yearsn=1694n=1694

ObservationObservationn=1693n=1693

Patient CharacteristicsPatient Characteristics

Piccart et al. N Engl J Med 2005 Oct 20;353(16):1659-72.

HERA Disease Free SurvivalHERA Disease Free Survival

Trastuzumab 1 yrTrastuzumab 1 yr

ObservationObservation% alive and % alive and disease freedisease free

100100

9090

8080

7070

6060

Months from randomizationMonths from randomization00 55 1010 1515 2020 2525

EventsEvents22--yryrDFS %DFS % HRHR [95% CI][95% CI] p valuep value

127127 85.885.8 0.540.54 [0.43, 0.67][0.43, 0.67] <0.0001<0.0001

220220 77.477.4

disease freedisease free 6060

5050

4040

3030

2020

1010

00


Median 1.5 year FU

HERA Trial DFS According to SubgroupsHERA Trial DFS According to SubgroupsHR: Trastuzumab 1 year vs observationHR: Trastuzumab 1 year vs observation

All

Any, neo-adjuvant chemotherapyNodal status

0 pos, no neo-adjuvant chemotherapy

3387

358

1100

872

203

2307

n

0.54

0.53

0.52

0.77

0.64

0.43

Hazardratio

1-3 pos, no neo-adjuvant chemotherapy

≥≥≥≥4 pos, no neo-adjuvant chemotherapy

No anthracycline or taxane

Adjuvant chemotherapy regimen

Anthracycline, no taxane

Anthracycline + taxaneReceptor status/endocrine therapy

972

953

0.51

0.53

All

Any, neo-adjuvant chemotherapyNodal status

0 pos, no neo-adjuvant chemotherapy

3387

358

1100

872

203

2307

n

0.54

0.53

0.52

0.77

0.64

0.43

Hazardratio

1-3 pos, no neo-adjuvant chemotherapy

≥≥≥≥4 pos, no neo-adjuvant chemotherapy

No anthracycline or taxane

Adjuvant chemotherapy regimen

Anthracycline, no taxane

Anthracycline + taxaneReceptor status/endocrine therapy

972

953

0.51

0.53

0 1 2

Negative

Receptor status/endocrine therapy

Pos + no endocrine therapy

Pos + endocrine therapy

<35 yrs

Age group

35-49 yrs

50-59 yrs

≥≥≥≥60 yrs

Europe, Nordic, Canada, SA, Aus, NZ

Region

Asia Pacific, Japan

Eastern Europe

Central + South America

1674 0.51

467

1234

0.49

0.68

251 0.47

1490

1091

0.52

0.53

549 0.70

2430 0.58

405

364

0.42

0.31

188 0.90

NZ, New Zealand;SA, South Africa

Favorstrastuzumab

Favorsobservation

0 1 2

Negative

Receptor status/endocrine therapy

Pos + no endocrine therapy

Pos + endocrine therapy

<35 yrs

Age group

35-49 yrs

50-59 yrs

≥≥≥≥60 yrs

Europe, Nordic, Canada, SA, Aus, NZ

Region

Asia Pacific, Japan

Eastern Europe

Central + South America

1674 0.51

467

1234

0.49

0.68

251 0.47

1490

1091

0.52

0.53

549 0.70

2430 0.58

405

364

0.42

0.31

188 0.90

NZ, New Zealand;SA, South Africa

Favorstrastuzumab

Favorsobservation


Developments in HERA TrialDevelopments in HERA Trialsince ASCO 2005since ASCO 2005

•• Median FU now 2 yearsMedian FU now 2 years•• (median 1 year at ASCO 2005)(median 1 year at ASCO 2005)

•• 539 events observed in the 2 arms539 events observed in the 2 arms•• (347 at ASCO 2005)(347 at ASCO 2005)

•• After ASCO 2005, switch to trastuzumab After ASCO 2005, switch to trastuzumab •• (347 at ASCO 2005)(347 at ASCO 2005)

•• After ASCO 2005, switch to trastuzumab After ASCO 2005, switch to trastuzumab offered to control armoffered to control arm•• As of 15th May 2006 861 observation patients As of 15th May 2006 861 observation patients are known to have switched to trastuzumabare known to have switched to trastuzumab

•• Therefore 2 analyses now possible Therefore 2 analyses now possible •• ITTITT•• Censored at time of switchCensored at time of switch

100100

8080

6060

4040

Patients(%)Patients(%)

1 year trastuzumab1 year trastuzumab

ObservationObservation

DiseaseDisease--free survival (ITT)free survival (ITT)

EventsEvents HRHR 95% CI95% CI p valuep value33--yearyearDFSDFS

6.3%6.3%

Median FU 2 yrsMedian FU 2 yrs

17031703 11591591 14341434 11271127 742742 383383 140140

16981698 11535535 13301330 984984 639639 334334 127127

4040

2020

00

Months from randomisationMonths from randomisation

1122 363600 118866

No. No. at risk at risk

2424 3030

EventsEvents HRHR 95% CI95% CI p valuep value

0.640.64 0.54, 0.760.54, 0.76 <0.0001<0.0001

DFSDFS

80.680.6

74.374.3

218218

321321

Smith et al. Proc ASCO 2006

100100

8080

6060

4040

Patients(%)Patients(%)


Overall survival (ITT)Overall survival (ITT)

1 year trastuzumab1 year trastuzumab

EventsEvents HRHR 95% CI95% CI p valuep value33--yearyearOSOS

Median FU 2 yrsMedian FU 2 yrs

2.7%2.7%

17031703 16271627 14981498 11901190 794794 407407 146146

4040

2020

00

Months from randomisationMonths from randomisation

No. No. at risk at risk 16981698 11608608 14531453 10971097 711711 366366 139139

EventsEvents HRHR 95% CI95% CI p valuep value

0.660.66 0.47, 0.910.47, 0.91 0.01150.0115

OSOS

92.492.4

89.789.7

1122 363600 118866 2424 3030

5959

9090


Exploratory DFS subgroup analysis (ITT):Exploratory DFS subgroup analysis (ITT):1 year trastuzumab vs observation1 year trastuzumab vs observation

<35 years (253)<35 years (253) 19 vs 3119 vs 31 0.57 (0.32, 1.01)0.57 (0.32, 1.01)

3535--49 years (1508)49 years (1508) 89 vs 15089 vs 150 0.54 (0.42, 0.70)0.54 (0.42, 0.70)

5050--59 years (1096)59 years (1096) 71 vs 9771 vs 97 0.71 (0.52, 0.97)0.71 (0.52, 0.97)

Age at randomisationAge at randomisation

No. eventsNo. eventsT vs obsT vs obs

HR (95% CI)HR (95% CI)Subgroup (no. patients)Subgroup (no. patients)

ERER--negative + PgRnegative + PgR--negative (1627)negative (1627) 126 vs 190126 vs 190 0.63 (0.50, 0.78)0.63 (0.50, 0.78)ERER--negative + PgRnegative + PgR--positive (172)positive (172) 0.77 (0.34, 1.74)0.77 (0.34, 1.74)12 vs 1212 vs 12ERER--positive + PgRpositive + PgR--negative (460)negative (460) 26 vs 3926 vs 39 0.82 (0.50, 1.34)0.82 (0.50, 1.34)ERER--positive + PgRpositive + PgR--positive (984)positive (984) 46 vs 6146 vs 61 0.63 (0.43, 0.93)0.63 (0.43, 0.93)

Tumour Hormone Receptor statusTumour Hormone Receptor status

0.00.0 0.50.5 1.01.0 1.51.5

5050--59 years (1096)59 years (1096) 71 vs 9771 vs 97 0.71 (0.52, 0.97)0.71 (0.52, 0.97)

>>60 years (544)60 years (544) 39 vs 4339 vs 43 0.91 (0.59, 1.41)0.91 (0.59, 1.41)

Premenopausal (491)Premenopausal (491) 43 vs 4943 vs 49 0.80 (0.53, 1.21)0.80 (0.53, 1.21)

Uncertain (1373)Uncertain (1373) 70 vs 13570 vs 135 0.48 (0.36, 0.64)0.48 (0.36, 0.64)

Postmenopausal (1535)Postmenopausal (1535) 105 vs 137105 vs 137 0.75 (0.58, 0.97)0.75 (0.58, 0.97)

neoadjuvant CT (372)neoadjuvant CT (372) 39 vs 5039 vs 50 0.66 (0.43, 1.00)0.66 (0.43, 1.00)

Negative (1099)Negative (1099) 34 vs 5834 vs 58 0.59 (0.39, 0.91)0.59 (0.39, 0.91)

11--3 positive nodes (976)3 positive nodes (976) 50 vs 8050 vs 80 0.61 (0.43, 0.87)0.61 (0.43, 0.87)

Nodal statusNodal status

Menopausal status at randomisationMenopausal status at randomisation

>>4 positive nodes (953)4 positive nodes (953) 95 vs 13295 vs 132 0.64 (0.49, 0.83)0.64 (0.49, 0.83)

All patients (3401)All patients (3401) 218 vs 321218 vs 321 0.64 (0.54, 0.76)0.64 (0.54, 0.76)

H RH ROverall ResultOverall Result

Site of 1st diseaseSite of 1st disease--free survival eventfree survival event(ITT Analysis)(ITT Analysis)

Total no. events

Distant event

Observation(n=1698)

321 (18.9)

233 (13.7)

1 year trastuzumab(n=1703)

218 (12.8)

152 (8.9)

No. events (%)

Distant event

Central Nervous System

Locoregional event

Contralateral breast cancer

2nd non-breast malignancy

Death as 1st event

233 (13.7)

22 (1.3)

68 (4.0)

9 (0.5)

8 (0.5)

3 (0.2)

152 (8.9)

26 (1.5)

45 (2.6)

7 (0.4)

6 (3.5)

8 (4.7)

?


↑↑↑↑ ↑↑↑↑

BCIRG 006: SchemaBCIRG 006: Schema

N=3222N=3222

Node + /Node + /HighHigh--risk noderisk node––FISH+FISH+

(q3w x 4)(q3w x 4) (q3w x 4)(q3w x 4)

(q3w x 14)(q3w x 14)

↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑

↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑

Slamon D, SABCS 2005

↑↑↑↑↑↑↑↑ Trastuzumab 4mg/kg first wk; Trastuzumab 4mg/kg first wk; ↑↑↑↑↑↑↑↑ Trastuzumab 2mg/kg qw; Trastuzumab 2mg/kg qw; ↑↑↑↑↑↑↑↑ Trastuzumab Trastuzumab 6mg/kg q3w6mg/kg q3w

Taxotere 100mg/mTaxotere 100mg/m22 q3wq3wA 60mg/mA 60mg/m22 + C 600mg/m+ C 600mg/m22 q3w;q3w;Carboplatin AUC 6 or Cisplatin 75mg/mCarboplatin AUC 6 or Cisplatin 75mg/m22 + Taxotere 75mg/m+ Taxotere 75mg/m22 q3wq3w

N=3222N=3222(qw x 12)(qw x 12)

(q3w x 14)(q3w x 14)(q3w x 6)(q3w x 6)

(q3w x 12)(q3w x 12)(qw x 18)(qw x 18)

↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ ↑↑↑↑

Stratified by Nodes Stratified by Nodes and Hormonal and Hormonal Receptor StatusReceptor Status

Patient characteristicsPatient characteristics

Randomized Randomized (n=3,222)(n=3,222)

ACAC--TTn=1,073n=1,073

ACAC--THTHn=1,074n=1,074

TCHTCHn=1,075n=1,075

%% %% %%

Age < 50 yearsAge < 50 years 52 52 5252 5454Age < 50 yearsAge < 50 years 52 52 5252 5454

KPS = 100KPS = 100 80 80 7979 80 80

MastectomyMastectomy 60 60 6363 60 60

RadiotherapyRadiotherapy 59 59 5858 60 60

HormonotherapyHormonotherapy 4747 4747 4949


Tumor CharacteristicsTumor Characteristics

Randomized Randomized (n=3,222)(n=3,222)

ACAC--TTn=1,073n=1,073

ACAC--THTHn=1,074n=1,074

TCHTCHn=1,075n=1,075

Number of nodes +Number of nodes + %% %% %%

00 29 29 29 29 29 29

1 1 –– 33 39 39 38 38 39 39

4 4 –– 1010 22 22 24 24 23 23 4 4 –– 1010 22 22 24 24 23 23

> 10> 10 11 11 9 9 10 10

Tumor Size (cm)Tumor Size (cm) %% %% %%

≤≤ 2 2 41 41 38 38 40 40

> > 2 and 2 and ≤≤ 55 53 53 55 55 54 54

> 5> 5 6 6 7 7 6 6

ER and/or PR +ER and/or PR + 54 54 54 54 54 54


Disease Free SurvivalDisease Free Survival% D

isea

se Free

% D

isea

se Free

0.8

0.8

0.9

0.9

1.0

1.0

81%81%

87%87%

86%86% 83%83%

82%82%87%87%

93%93%

92%92%

% D

isea

se Free

% D

isea

se Free

0.5

0.5

0.6

0.6

0.7

0.7

0.8

0.8

00 11 22 33 44 55

PatientsPatients EventsEvents

10731073 192192 ACAC-->T>T

10741074 128128 ACAC-->TH>TH

10751075 142142 TCHTCH

81%81%

77%77%

HR (ACHR (AC-->TH vs AC>TH vs AC-->T) = 0.61 [0.48;0.76] P<0.0001>T) = 0.61 [0.48;0.76] P<0.0001

HR (TCH vs ACHR (TCH vs AC-->T) = 0.67 [0.54;0.83] P=0.0003>T) = 0.67 [0.54;0.83] P=0.0003

Year from randomizationYear from randomization


Overall SurvivalOverall Survival% S

urvival

% S

urvival

0.8

0.8

0.9

0.9

1.0

1.0

97%97%

99%99%

98%98%

93%93%

97%97%

95%95% 92%92%

91%91%

86%86%

HR (ACHR (AC-->TH vs AC>TH vs AC-->T) = 0.59 [0.42;0.85] P=0.004>T) = 0.59 [0.42;0.85] P=0.004

HR (TCH vs ACHR (TCH vs AC-->T) = 0.66 [0.47;0.93] P=0.017>T) = 0.66 [0.47;0.93] P=0.017

% S

urvival

% S

urvival

0.5

0.5

0.6

0.6

0.7

0.7

00 11 22 33 44 55

PatientsPatients EventsEvents10731073 8080 ACAC-->T>T

10741074 4949 ACAC-->TH>TH

10751075 5656 TCHTCH

Year from randomizationYear from randomizationSlamon D, SABCS 2006

DFS SubpopulationsDFS Subpopulations

SubgroupSubgroup

Node negNode neg

Node posNode pos

HR HR --

ACAC--TH vs ACTH vs AC--TTSubgroupSubgroup

Node negNode neg

Node posNode pos

HR HR --

TCH vs ACTCH vs AC--TT

1.01.00.00.0 2.02.0

ACAC--THTHbetterbetter

ACAC--TTbetterbetter

HR HR --

HR +HR +

Tsize<2cmTsize<2cm

TsizeTsize≥≥2cm2cm

1.01.00.00.0 2.02.0

HR HR --

HR +HR +

Tsize<2cmTsize<2cm

TsizeTsize≥≥2cm2cm

TCHTCHbetterbetter

ACAC--TTbetterbetter


Fin Her trial designFin Her trial design

CISH +veCISH +ve

N=58N=58

N=54N=54

N=62N=62

Taxotere 100 or 80mg/mTaxotere 100 or 80mg/m22 FEFE6060CCVinorelbine 25 mg/mVinorelbine 25 mg/m22

CISH CISH --veve

Trastuzumab weekly for 9 weeksTrastuzumab weekly for 9 weeks

Joensuu et al. N Engl J Med 2006 Feb 23;354(8):809-820.

N=54N=54

N=53N=53

DiseaseDisease--free survival in the free survival in the FinHer trialFinHer trial

100100

8080

78%78%

89%89%TrastuzumabTrastuzumab

No trastuzumabNo trastuzumab

free survival (%

)free survival (%

)

6060

4040

2020

00

00 11 22 33 44

YearsYears

78%78%

Disease

Disease--free survival (%

)free survival (%

)

NN EventsEventsNo TrastuzumabNo Trastuzumab 116116 2727TrastuzumabTrastuzumab 115 12115 12

P=0.01P=0.01HR=0.42HR=0.42

Joensuu et al. N Engl J Med 2006 Feb 23;354(8):809-820.

Trastuzumab ConsistentlyTrastuzumab ConsistentlyReduces DFS EventsReduces DFS Events

HERAHERA 2 years2 years

Combined analysis BCombined analysis B--31/N983131/N9831 2 years2 years

Median followMedian follow--upup

2 years2 yearsBCIRG 006 AC BCIRG 006 AC DDHH

Piccart-Gebhart et al 2005; Romond et al 2005;Slamon et al 2005; Joensuu et al 2005

00 11 22FavorsFavorsTrastuzumabTrastuzumab

Favors noFavors noTrastuzumabTrastuzumab

HRHR

BCIRG 006 DCarboHBCIRG 006 DCarboH 2 years2 years

2 years2 yearsBCIRG 006 AC BCIRG 006 AC DDHH

FinHER VH / DH CEFFinHER VH / DH CEF 3 years3 years

Trastuzumab Following Adjuvant Chemotherapy Trastuzumab Following Adjuvant Chemotherapy in Patients With Node + / HER2in Patients With Node + / HER2--Postitive BC:Postitive BC:

FourFour--Year Results of the PACSYear Results of the PACS--04 Trial04 Trial

R1R1

SSUURRGG

Trastuzumab (T)Trastuzumab (T)Loading dose Loading dose 88--> 6mg /kg q 3 > 6mg /kg q 3 wks wks ffor 1 year or 1 year

RR22

6 6 FEC 100FEC 100q 3 wksq 3 wks

(1515 patients)(1515 patients)

N+N+

R1R1GGEERRYY


RR22

•• Second randomization:Second randomization: Central testing for HER2 statusCentral testing for HER2 status-- Eligibility criteria for trastuzumab:Eligibility criteria for trastuzumab: ≥ 4 cycles of previous ≥ 4 cycles of previous chemotherapy, adequate cardiac function, no metastaseschemotherapy, adequate cardiac function, no metastases-- Primary endpoint:Primary endpoint: 33--year DFSyear DFS

Spielmann, PA et al. SABCS 2007, Abstract 72

6 6 ED 75/75ED 75/75q 3 wksq 3 wks

(1495 patients)(1495 patients)

PACSPACS--04: Disease04: Disease--Free Survival Free Survival (ITT)(ITT)

0.50

0.75

1.00

Pro

babili

ty

HR=0.86: 95%CI [0.61-1.22]

Kaplan-Meier survival estimatesKaplan-Meier curves, and log-rank test stratified on N

80.9%

77.9%

72.7 %

73.2%

HR = 0.86; 95%CI [0.61-1.22]

0.00

0.25

Pro

babili

ty

260 251 221 149 78 10Trastuzumab268 250 225 168 93 21Observation

Number at risk

0 12 24 36 48 60Months

Observation Trastuzumab p=0.41

HR = 0.86; 95%CI [0.61-1.22]

P = 0.41


Summary of Trastuzumab Adjuvant TrialsSummary of Trastuzumab Adjuvant Trials

HRHR

0.540.54

0.640.64

0.480.48

StudyStudy FU, FU, yrsyrs

PtsPts

HERAHERA

11 3,3873,387

22 3,4013,401

NSABP BNSABP B--31/31/

NCCTG 9831NCCTG 9831

22 3,3513,351

44 3,9683,968

0.800.80HERA: Anthracycline/Taxane Chemo HERA: Anthracycline/Taxane Chemo

00 11 22In favor of TIn favor of T

In favor of Obs.In favor of Obs.

0.480.48

0.870.87

0.610.61

0.420.42

0.860.86

NCCTG 9831NCCTG 9831 44 3,9683,968

NCCTG 9831 seqNCCTG 9831 seq

BCIRG 006BCIRG 006

1.51.5

33

1,9641,964

3,2223,222

FinHerFinHer 33 231231

PACS 04PACS 04 44 528528


Summary of cardiac toxicity in the randomized trials of Summary of cardiac toxicity in the randomized trials of adjuvant trastuzumab adjuvant trastuzumab

TrialTrial TreatmentTreatment Cardiac FollowCardiac Follow--upup AsymptomaticAsymptomatic↓↓↓↓↓↓↓↓ >>10% LVEF10% LVEF

Heart Failure Heart Failure Class III/IVClass III/IV

Cardiac DeathsCardiac Deaths

NSABP B-31Median f/u =

3 years

AC→→→→PAC→→→→P+H

MUGA scan 3 weeks after last AC dose, 6 and 9 months from randomization, and 3 months after the last trastuzumab dose.

17%34%

0.8%4.1%

0.1%0%

NCCTG N9831Median f/u =

2 years

AC→→→→PAC→→→→P+H→→→→HAC→→→→P→→→→H

MUGA scan or echocardiogram 3 weeks after last AC dose, 6, 9, and 18 months from randomization, and 3 months after last trastuzumab dose.

6.7%14.2%16.3%

0.3%2.5%3.5%

HERAMedian f/u =

1 year

ChemoChemo→→→→H

MUGA scan or echocardiogram at 3 to 4 weeks prior to randomization, and 3, 6, 12,

2.2%7.1%

0.06%1.73%

0.06%0%

1 year randomization, and 3, 6, 12, 18, 24, 30, 36, and 60 months from randomization.

BCIRG 006Median f/u = 23 months

AC→→→→T AC→→→→T+H

TCH

After last AC dose, after second docetaxel dose, after end of chemotherapy, and at 3, 12 and 36 months from randomization.

At baseline, at 6 weeks, 4.5 months, 13.5 months, and 37.5 months from randomization.

8%17.3%

9%

0.29%1.59%

0.38%

0%0%

0%

FinHerMedian f/u =

3 years

T→→→→CEFV→→→→CEF TH→→→→CEFVH→→→→CEF

MUGA scan or echocardiogram before chemotherapy, after FEC and 12 and 36 months after completion of chemotherapy

6.0%

3.5%

2.59%

0.27%

0%

0%

Gonzalez-Angulo et al. The Oncologist 2006

BB--31 Arm 2 / N9831 Arm C31 Arm 2 / N9831 Arm CAC Paclitaxel + TrastuzumabAC Paclitaxel + Trastuzumab

0mo.

18mos.

6mos.

9mos.

3mos.

LVEF Evaluation ScheduleLVEF Evaluation Schedule

BB--31 Arm 1 / N9831 Arm A31 Arm 1 / N9831 Arm AAC PaclitaxelAC Paclitaxel

0mo.

18mos.

6mos.

9mos.

3mos.


Criteria for Managing Trastuzumab Criteria for Managing Trastuzumab inin Asymptomatic PatientsAsymptomatic Patients

Six and Nine Month Six and Nine Month LVEF ValueLVEF Value

Relationship of 6 and 9 Month LVEF Relationship of 6 and 9 Month LVEF Value to Baseline LVEF Value Value to Baseline LVEF Value

Absolute Absolute ��of < 10 % of < 10 % PointsPoints

Absolute Absolute ��of 10of 10--15 15 % % PointsPoints

Absolute Absolute ��of > 15 % of > 15 % PointsPoints

At or Above LLNAt or Above LLN ContinueContinue ContinueContinue Hold *Hold *

1 1 -- 55 % Points below % Points below LLNLLN

ContinueContinue Hold *Hold * Hold *Hold *

> 5> 5 % Points below LLN% Points below LLN Continue*Continue* Hold *Hold * Hold *Hold *

* Repeat MUGA after 4 weeks * Repeat MUGA after 4 weeks

If criteria for continuation met If criteria for continuation met –– resume trastuzumab resume trastuzumab

If 2 consecutive holds, or total of 3 holds occur If 2 consecutive holds, or total of 3 holds occur –– D/C trastuzumabD/C trastuzumab

Case PresentationCase Presentation

•• 36 y/o female who presents with stage I 36 y/o female who presents with stage I breast cancer (T1a N0 M0), s/p breast cancer (T1a N0 M0), s/p lumpectomy & SLNB. The cancer cells are lumpectomy & SLNB. The cancer cells are ERER--, HER2+ (FISH ratio = 8). The size of , HER2+ (FISH ratio = 8). The size of the invasive tumor is 0.4 cm.the invasive tumor is 0.4 cm.the invasive tumor is 0.4 cm.the invasive tumor is 0.4 cm.

•• Should this patient be considered for Should this patient be considered for adjuvant adjuvant trastuzumabtrastuzumab--based chemotherapy?based chemotherapy?

High Risk of Recurrence for Breast High Risk of Recurrence for Breast Cancer Patients with HER2Cancer Patients with HER2--Positive Positive

Node Negative Tumors 1 cm or SmallerNode Negative Tumors 1 cm or Smaller

•• 965 node965 node--negative invasive breast cancers ≤ 1 cm seen at negative invasive breast cancers ≤ 1 cm seen at M. D. Anderson Cancer Center from 1990 to 2002M. D. Anderson Cancer Center from 1990 to 2002

•• No adjuvant chemotherapy or No adjuvant chemotherapy or trastuzumabtrastuzumab

•• Distribution by ER/PR and HERDistribution by ER/PR and HER--22•• 77% HR77% HR--positivepositive•• 13% Triple negative13% Triple negative•• 10% HER210% HER2--positivepositive

•• Dedicated breast pathologists confirmed HER2Dedicated breast pathologists confirmed HER2--positivity by positivity by IHC (3+) and/or FISH (her2:cep17 IHC (3+) and/or FISH (her2:cep17 >> 2.0)2.0)

Gonzalez-Angulo AM, et al. J Clin Oncol, in press (2009)

MDACC Patient CharacteristicsMDACC Patient Characteristics HER2-Negative HER2-Positive P-Value

N Percent N Percent

N 867 -- 98 -- Age

Minimal 26 -- 28 -- Median 57 -- 51.5 -- Maximal 87 -- 78 -- <0.0001

Race Black 61 7.0 9 9.2 Hispanic 78 9.0 10 10.2 Other 35 4.0 4 4.1 White 693 79.9 75 76.5 0.843

Menopausal Status Status

Pre 201 23.2 43 43.9 Post 665 76.8 55 56.1 <0.0001

Histology Other 206 23.8 8 8.2 Ductal 661 76.2 90 91.8 0.0004

T Stage Ia 280 32.3 43 43.9 Ib 587 67.7 55 56.1 0.021

Hormone Receptor

Negative 125 14.4 38 38.8 Positive 742 85.6 60 61.2 <0.0001

Nuclear Grade 1 116 17.3 1 1.5 2 386 57.6 17 25.4 3 168 25.1 49 73.1 <0.0001


HER2HER2--positive (%)positive (%)

HER2HER2--negative (%)negative (%)

P valueP value

7777 9494 <0.001<0.001

High Risk of Recurrence for Breast High Risk of Recurrence for Breast Cancer Patients with HER2Cancer Patients with HER2--Positive Positive

Node Negative Tumors 1 cm or SmallerNode Negative Tumors 1 cm or Smaller

55--yr RFSyr RFS7777 9494 <0.001<0.001

55--YR DRFSYR DRFS8686 9797 <0.001<0.001


p<0.0001p<0.0001

HER2-Positive 21 77.1% (67%, 84.5%)

p<0.0001p<0.0001

RFSRFS

MDACC Survival EstimatesMDACC Survival Estimates

Negative 51 93.7% (91.8%, 95.2%) Positive 21 77.1% (67%, 84.5%)

DRFSDRFS

Negative 22 97.2% (95.8%, 98.2%) Positive 12 86.4% (77.3%, 92.1%)

HER2-Positive 12 86.4% (77.3%, 92.1%) HR-Positive and HER2-Negative 17 97.5% (96%, 98.4%) Triple Receptor-Negative 5 95.6% (89.8%, 98.2%)

HER2-Positive 21 77.1% (67%, 84.5%) HR-Positive and HER2-Negative 33 95.2% (93.3%, 96.6%) Triple Receptor-Negative 18 85.2% (77.6%, 90.4%)

p<0.0001p<0.0001 p<0.0001p<0.0001


Multivariate AnalysisMultivariate Analysis

RecurrenceRecurrence--Free SurvivalFree SurvivalDistant RecurrenceDistant Recurrence--Free Free

SurvivalSurvival

HazardHazardRatioRatio

95% 95% ConfidenceConfidenceIntervalInterval PP--ValueValue

HazardHazardRatioRatio

95% 95% ConfidenceConfidenceIntervalInterval PP--ValueValue

HER2 Positive HER2 Positive vs. Negativevs. Negative 2.682.68 (1.44, 5)(1.44, 5) 0.0020.002 5.305.30(2.23, (2.23, 12.62)12.62) 0.00020.0002HER2 Positive HER2 Positive vs. Negativevs. Negative 2.682.68 (1.44, 5)(1.44, 5) 0.0020.002 5.305.30 12.62)12.62) 0.00020.0002

HR Positive versus NegativeHR Positive versus Negative 0.410.41 (0.23, 0.72)(0.23, 0.72) 0.0020.002 0.590.59 (0.25, 1.37)(0.25, 1.37) 0.2190.219

Age at Diagnosis (Continuous)Age at Diagnosis (Continuous) 0.960.96 (0.94, 0.98)(0.94, 0.98) 0.0010.001 0.730.73 (0.32, 1.7)(0.32, 1.7) 0.4670.467

Grade 3 versus Grade 1Grade 3 versus Grade 1--22 1.341.34 (0.75, 2.41)(0.75, 2.41) 0.3200.320 0.970.97 (0.94, 1)(0.94, 1) 0.0800.080

Stage Ib versus Stage IaStage Ib versus Stage Ia 1.591.59 (0.91, 2.78)(0.91, 2.78) 0.1030.103 1.471.47 (0.68, 3.18)(0.68, 3.18) 0.3290.329


ConclusionsConclusions

•• Adjuvant Adjuvant trastuzumabtrastuzumab improves diseaseimproves disease--free survival in free survival in patients with HER2+ invasive breast cancer regardless of patients with HER2+ invasive breast cancer regardless of lymph node statuslymph node status

•• Most patients with nodeMost patients with node--negative breast cancer enrolled in negative breast cancer enrolled in adjuvant adjuvant trastuzumabtrastuzumab trials had tumors larger than 1 cmtrials had tumors larger than 1 cm

•• Patients with HER2Patients with HER2--positive tumors ≤ 1 cm (T1a, T1b) have positive tumors ≤ 1 cm (T1a, T1b) have a significant risk of relapse and should be considered for a significant risk of relapse and should be considered for a significant risk of relapse and should be considered for a significant risk of relapse and should be considered for systemic antisystemic anti--HER2 adjuvant therapyHER2 adjuvant therapy

•• Questions:Questions: Duration?Duration?

With or after chemotherapy?With or after chemotherapy?

Integration of new targeted agents?Integration of new targeted agents?

•• Mechanism(s) of Mechanism(s) of trastuzumabtrastuzumab resistanceresistance

Neoadjuvant Trastuzumab for Neoadjuvant Trastuzumab for Early HER2Early HER2--positive Breast positive Breast

CancerCancerCancerCancer

MDACC 99MDACC 99--146146

VSVS

Paclitaxel Paclitaxel (P) = 225 mg/m(P) = 225 mg/m22 24 hr IV 24 hr IV infusion Q 3 weeks X 4infusion Q 3 weeks X 4

FECFECFluorouracilFluorouracil 500 mg/m2 IV day 1 & 4500 mg/m2 IV day 1 & 4EpirubicinEpirubicin 75 mg/m2 IV day 75 mg/m2 IV day

FFEECC

FFEECC

FFEECC

FFEECC

PPPPPPPP

++

EpirubicinEpirubicin 75 mg/m2 IV day 75 mg/m2 IV day 1 only1 only

CyclophosphamideCyclophosphamide 500 mg/m2 IV day 500 mg/m2 IV day 1 only Q 3 weeks X 41 only Q 3 weeks X 4

Trastuzumab (H) = 4 mg/kg IV day Trastuzumab (H) = 4 mg/kg IV day 1, then 2 mg/kg IV weekly X 24 1, then 2 mg/kg IV weekly X 24 weekweek

FFEECC

FFEECC

FFEECC

FFEECC

PPPPPPPP

Buzdar, J Clin Oncol, 2005

Response RatesResponse Rates

Buzdar AU, SABCS 2005

ToxicityToxicity

Randomized PatientsRandomized Patients Assigned RxAssigned Rx

RxRx PP→→→→→→→→FECFEC

1919

PP→→→→→→→→FEC + HFEC + H

2323

PP→→→→→→→→FEC + HFEC + H

2222

NeutropeniaNeutropenia

Grade 4Grade 4 1111 2121 2020

InfectionsInfections 33 55 44

HospitalizationsHospitalizations 11 33 55

Allergic ReactionsAllergic Reactions 44 77 88

CT Dose ReductionsCT Dose Reductions 44 44 77

Cardiac DysfunctionCardiac Dysfunction

Asympt Asympt ↓↓↓↓↓↓↓↓ 10% LVEF10% LVEF

CHFCHF

55

1 (NY HC 3)1 (NY HC 3)

77

00

66

1 (NY HC 1)1 (NY HC 1)

Buzdar AU, SABCS 2005

NOAH: the largest neoadjuvant trial NOAH: the largest neoadjuvant trial in HER2in HER2--positive breast cancerpositive breast cancer

HER2HER2--positive LABCpositive LABC(IHC 3+ and / or FISH+)(IHC 3+ and / or FISH+)

n=113n=113

H + ATH + ATq3w x 3q3w x 3

H + TH + Tq3w x 4q3w x 4

TTq3w x 4q3w x 4

n=115n=115

ATATq3w x 3q3w x 3

ATATq3w x 3q3w x 3

TTq3w x 4q3w x 4

n=99n=99

HER2HER2--negative LABCnegative LABC(IHC 0/1+)(IHC 0/1+)

aaHormone receptorHormone receptor--positive patients receive adjuvant tamoxifen; LABC, locally advanced breast cancer; H, positive patients receive adjuvant tamoxifen; LABC, locally advanced breast cancer; H, trastuzumab (8 mg/kg loading then 6 mg/kg); AT, doxorubicin (60 mg/mtrastuzumab (8 mg/kg loading then 6 mg/kg); AT, doxorubicin (60 mg/m22), paclitaxel (150 mg/m), paclitaxel (150 mg/m22); ); T, paclitaxel (175 mg/mT, paclitaxel (175 mg/m22); CMF, cyclophosphamide, methotrexate, fluorouracil); CMF, cyclophosphamide, methotrexate, fluorouracil

q3w x 4q3w x 4

H q3w x 4 H q3w x 4 + CMF q4w x 3+ CMF q4w x 3

Surgery followed bySurgery followed byradiotherapyradiotherapyaa

H continued q3wH continued q3wto Week 52to Week 52

q3w x 4q3w x 4

CMFCMFq4w x 3q4w x 3


q3w x 4q3w x 4

CMFCMFq4w x 3q4w x 3


Efficacy: Efficacy: total and IBC populationtotal and IBC population

(n=99)(n=99)

65.765.7

1717

Total populationTotal population

Overall response rateOverall response rate

pCRpCR

HER2HER2--positive, %positive, %

--HH+H+H

(n=113)(n=113)

73.473.4

2323

(n=115)(n=115)

80.980.9

4343

HER2HER2--negative, %negative, %ResponseResponse

1717

1616

(n=14)(n=14)

57.157.1

2929

2929

pCRpCR

tpCRtpCR

IBC populationIBC population

Overall response rate Overall response rate

pCRpCR

tpCRtpCR

2323

2020

(n=31)(n=31)

77.477.4

1919

1313

4343

3838

(n=31)(n=31)

77.477.4

5555

4848

tpCR, total pCR in breast and nodestpCR, total pCR in breast and nodes

Significant improvement of pCR Significant improvement of pCR in IBC by adding trastuzumabin IBC by adding trastuzumab

20

30

40

50

60PatientsPatients(%)(%)

p=0.004p=0.004p=0.002p=0.002

44(29%)(29%)

1717(55%)(55%)

44(29%)(29%)

1515(48%)(48%)p=0.49p=0.49 p=0.20p=0.20

+H+H--HH0

10

20

HER2HER2negativenegative

+H+H HER2HER2negativenegative

--HH

HER2 positiveHER2 positive HER2 positiveHER2 positive

tpCRtpCRpCRpCR

(29%)(29%)66

(19%)(19%)

(29%)(29%)

44(13%)(13%)

eradication of invasive eradication of invasive cancer in the breastcancer in the breast

eradication of invasive eradication of invasive cancer in the breast cancer in the breast plus axillary nodesplus axillary nodes

Trastuzumab for HER2Trastuzumab for HER2--positive positive Metastatic Breast CancerMetastatic Breast Cancer

Trastuzumab in the Treatment of Trastuzumab in the Treatment of HER2+ MBCHER2+ MBC

•• Trastuzumab is the first FDA approved targeted biologic Trastuzumab is the first FDA approved targeted biologic therapy for HER2+ MBC, September 1998therapy for HER2+ MBC, September 1998

•• Unparalleled opportunity for achieving statistically significant Unparalleled opportunity for achieving statistically significant and clinically meaningful:and clinically meaningful:•• Longer time to disease progressionLonger time to disease progression•• Higher rate of responseHigher rate of response•• Higher rate of responseHigher rate of response•• Longer duration of responseLonger duration of response•• Improved overall survival Improved overall survival

•• Well characterized safety profile in more than 312,000 Well characterized safety profile in more than 312,000 patients treated worldwide and more than 8 years of clinical patients treated worldwide and more than 8 years of clinical experienceexperience

Therapy of HER2Therapy of HER2--Positive Positive Metastatic Breast CancerMetastatic Breast Cancer

Trastuzumab MonotherapyTrastuzumab MonotherapyTrastuzumab MonotherapyTrastuzumab Monotherapy

Trastuzumab FirstTrastuzumab First--Line Monotherapy Line Monotherapy Trial in MBC: SchemaTrial in MBC: Schema

•• N=114N=114

•• Measurable metastatic diseaseMeasurable metastatic disease

•• HER2 overexpression (2+/3+)HER2 overexpression (2+/3+)

•• No prior chemotherapy for MBCNo prior chemotherapy for MBC

•• KPSKPS≥≥≥≥≥≥≥≥70%70%

Weekly trastuzumabWeekly trastuzumab

4 mg/kg loading dose4 mg/kg loading dose

2 mg/kg/wk maintenance2 mg/kg/wk maintenance

Primary end point:Primary end point: ORRORRSecondary end points:Secondary end points: DOR, TTP, survival, QOLDOR, TTP, survival, QOL

Weekly trastuzumabWeekly trastuzumab

8 mg/kg loading dose8 mg/kg loading dose

4 mg/kg/wk maintenance4 mg/kg/wk maintenance

Vogel et al. J Clin Oncol. 2002;20:719.

RANDOMIZERANDOMIZE

ObjectiveObjective ClinicalClinicalPatient SubsetPatient Subset Response (%)Response (%) Benefit (%)*Benefit (%)*

All assessable, n=111All assessable, n=111 26 (18.026 (18.0--34.3)34.3)†† 3838

HER2 3+ (n=84)HER2 3+ (n=84) 3535 4848

Trastuzumab FirstTrastuzumab First--Line Monotherapy:Line Monotherapy:Tumor Response and Clinical BenefitTumor Response and Clinical Benefit

by HER2 Statusby HER2 Status

HER2 2+ (n=27)HER2 2+ (n=27) 00 77

FISH+ (n=79)FISH+ (n=79) 3434 4848

FISHFISH–– (n=29)(n=29) 77 1010

*Clinical benefit = complete, partial, and minor responses, plus stable disease *Clinical benefit = complete, partial, and minor responses, plus stable disease >6 months.>6 months.††95% confidence interval.95% confidence interval.


Trastuzumab FirstTrastuzumab First--Line Monotherapy: Line Monotherapy: KaplanKaplan--Meier Estimates of Time to Meier Estimates of Time to Progression for FISH+ vs FISHProgression for FISH+ vs FISH––

Median TTPMedian TTP

FISH+ FISH+ 4.9 mo4.9 moFISH FISH –– 1.7 mo1.7 mo

Prob

ability

Prob

ability 0.6

0.8

1.0 IHC 2+ or 3+ (n=108)IHC 2+ or 3+ (n=108)

FISH+ (n=79)FISH+ (n=79)

FISHFISH–– (n=29)(n=29)


FISH FISH –– 1.7 mo1.7 mo

PP<0.0001<0.0001

0 10 20 30 40

TTP (mo) TTP (mo)

Prob

ability

Prob

ability

0

0.2

0.4

Trastuzumab Monotherapy Trials:Trastuzumab Monotherapy Trials:Summary of EfficacySummary of Efficacy

Prior CTPrior CT

Regimens for Regimens for MBCMBC RefRef OverallOverall FISH+ FISHFISH+ FISH–– IHC 3+IHC 3+

NoneNone Vogel et al,Vogel et al,20022002

111111 26*26* 34 734 7 3535

NoneNone Baselga et al,Baselga et al, 105105 1919†† –– –– ––

Response Rate (%) Response Rate (%)

*All patients were HER2+ by IHC; trastuzumab treatment was qw.*All patients were HER2+ by IHC; trastuzumab treatment was qw.††All patients were HER2 IHC 3+ or FISH+; trastuzumab treatment was q3w.All patients were HER2 IHC 3+ or FISH+; trastuzumab treatment was q3w.

Vogel et al. J Clin Oncol. 2002;20:719; Baselga et al. J Clin Oncol. 2005;23:2162; Cobleigh et al. J Clin Oncol. 1999;17:2639; Baselga et al. J Clin Oncol. 1996;14:737.

NoneNone Baselga et al,Baselga et al,20052005

105105 1919†† –– –– ––

1 1 –– 22 Cobleigh et al,Cobleigh et al,19991999

222222 15*15* 1919 00 1818

0 0 -- >2>2 Baselga et al, Baselga et al, 19961996

4343 11.6*11.6* –– –– ––

Case PresentationCase Presentation

•• 57 y/o female who presents with stage IV 57 y/o female who presents with stage IV breast cancer (2 liver lesions and bone breast cancer (2 liver lesions and bone metastasis) after 2 years of completing metastasis) after 2 years of completing chemotherapy with AC x 4 for a (T1c N0 chemotherapy with AC x 4 for a (T1c N0 M0), s/p lumpectomy & SLNB. M0), s/p lumpectomy & SLNB. M0), s/p lumpectomy & SLNB. M0), s/p lumpectomy & SLNB.

•• The cancer cells (liver The cancer cells (liver metsmets) are ER+, ) are ER+, HER2+ (FISH ratio = 8). HER2+ (FISH ratio = 8).

•• Should this patient be considered for Should this patient be considered for trastuzumabtrastuzumab--based chemotherapy?based chemotherapy?

CrossCross--talk between signal transduction talk between signal transduction and endocrine pathwaysand endocrine pathways

SOSSOSRASRAS

RAFRAFPI3PI3--KK

PPPP

PPPPPP

PPPlasmaPlasma

membranemembrane

AnastrozoleAnastrozole

HER2HER2

IGFRIGFRGrowth factorGrowth factorEstrogenEstrogen TrastuzumabTrastuzumab

Adapted from Johnston 2005

RAFRAF

BasalBasaltranscriptiontranscriptionmachinerymachineryp160p160

EREERE ER target gene transcriptionER target gene transcription

ERER CBPCBPPPPP PP PP

ERER

PPp90p90RSKRSK

AktAktPP

MAPKMAPKPP

CellCellsurvivalsurvival

CytoplasmCytoplasm

NucleusNucleus

ERER

CellCellgrowthgrowth

MEKMEKPP

TAnDEM Study DesignTAnDEM Study Design

HER2+, hormone HER2+, hormone receptorreceptor--positive positive MBC (n=208*)MBC (n=208*)

R

Anastrozole 1 mg/day +Anastrozole 1 mg/day +trastuzumab 4 mg/kg loading trastuzumab 4 mg/kg loading

dosedose→→→→→→→→2 mg/kg qw 2 mg/kg qw

until disease progressionuntil disease progression

•• Crossover to receive trastuzumab was actively offered to all Crossover to receive trastuzumab was actively offered to all patients who progressed on anastrozole alonepatients who progressed on anastrozole alone

MBC (n=208*)MBC (n=208*)

Anastrozole 1 mg/day Anastrozole 1 mg/day until disease progressionuntil disease progression

*1 patient did not receive study drug and was excluded from analyses.*1 patient did not receive study drug and was excluded from analyses.

Mackey JR, et al. Presented at: 29th Annual SABCS; Dec 14-17, 2006; San Antonio, Tex.

Baseline patient demographicsBaseline patient demographicsA+HA+H

(n=103)(n=103)

56 (3156 (31--85)85)

25.6 (0.625.6 (0.6--419)419)

1.6 (0.31.6 (0.3--67)67)

2 (12 (1--5)5)

4 (14 (1--14)14)

Age, yearsAge, years

Time from initial diagnosis, monthsTime from initial diagnosis, months

Duration of metastatic disease, monthsDuration of metastatic disease, months

No. metastatic sites/patientNo. metastatic sites/patient

No. lesions/patientNo. lesions/patient

Sites of metastases, % patientsSites of metastases, % patients

AA(n=104)(n=104)

54 (2754 (27--77)77)

27.3 (0.627.3 (0.6--154)154)

1.2 (0.31.2 (0.3--19)19)

2 (12 (1--5) 5)

4 (14 (1--13)13)

All data are median (range) unless otherwise noted; A, anastrozole; H, trastuzumabAll data are median (range) unless otherwise noted; A, anastrozole; H, trastuzumab

42423232626245457070

606053 53 4545

62 (5062 (50--82)82)

Sites of metastases, % patientsSites of metastases, % patientslunglungliverliverbonebonesoft tissuesoft tissueotherother

Previous therapy, % patients Previous therapy, % patients hormonalhormonalchemotherapy chemotherapy anthracyclineanthracycline

LVEF, %LVEF, %

46462828515142426363

666660 60 5151

63 (5163 (51--89)89)

ProgressionProgression--Free SurvivalFree SurvivalProb

ability

Prob

ability

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

EventsEvents Median PFSMedian PFS 95% CI95% CI pp--ValueValue

8787 4.8 months4.8 months 3.7, 7.03.7, 7.0 .0016.0016

9999 2.4 months2.4 months 2.0, 4.62.0, 4.6

PFS=time from randomization to date of progressive disease or death.PFS=time from randomization to date of progressive disease or death.


103103 4848 3131 1717 1414 1313 1111 99 44 11 11 00 00A+TA+T

104104 3636 2222 99 55 44 22 11 00 00 00 00 00AA

Number at riskNumber at risk

0.20.2

00 55 1010 1515 2020 2525 3030 3535 4040 4545 5050 5555 6060

MonthsMonths

0.00.0

2.4 months2.4 months

Clinical Benefit Rate in All Clinical Benefit Rate in All PatientsPatients

42.7%50

60

A+T (n=103)

A (n=104)

% of

% of

Patients

Patients

p=.026

27.9%

0

10

20

30

40

Clinical Benefit

% of

% of

Patients

Patients


Patients with measurable disease Patients with measurable disease evaluable for responseevaluable for response

PatientsPatients

A+T (n=74)A+T (n=74)

A (n=73)A (n=73)

4040

5050

6060

38.438.437.837.840.540.5

49.349.3

PatientsPatients(%)(%) p=0.018p=0.018

00

1010

2020

3030

4040

Partial responsePartial response Stable diseaseStable disease(>6 months)(>6 months)

Progressive diseaseProgressive disease

6.86.8

20.320.3

Overall SurvivalOverall SurvivalProb

ability

Prob

ability

1.01.0

0.0.88

0.60.6

0.40.4

EventsEvents Median PFSMedian PFS 95% CI95% CI pp--ValueValue

5858 28.5 28.5 monthsmonths

22.8, 22.8, 42.442.4

.325.325

6464 23.9 23.9 monthsmonths

18.2, 18.2, 37.437.4

73/104 patients (70%) received T later during the course of disease.73/104 patients (70%) received T later during the course of disease.


103103 9191 8383 7676 6363 4949 3636 2424 1212 44 33 00 00A+TA+T

104104 9696 8787 7373 5858 4242 3434 2222 55 22 11 11 00AA

Number at riskNumber at risk

00 55 1010 1515 2020 2525 3030 3535 4040 4545 5050 5555 6060MonthsMonths

0.20.2

0.00.0

Lesson from the Lesson from the TAnDEMTAnDEM TrialTrial

Therapy for HER2Therapy for HER2--Positive Positive Metastatic Breast CancerMetastatic Breast CancerMetastatic Breast CancerMetastatic Breast Cancer

Doublet Combinations of Doublet Combinations of Trastuzumab With Trastuzumab With ChemotherapyChemotherapy

SKSK--BRBR--33

BTBT--474474

MDAMDA--MBMB--361361


Combination indexCombination index

CarboplatinCarboplatin CyclophosphamideCyclophosphamide VinorelbineVinorelbine

DoxorubicinDoxorubicin EpirubicinEpirubicin00 11 22 00 11 22 00 11 22

Trastuzumab and Chemotherapy: Trastuzumab and Chemotherapy: Combination Index (CI) Scores for in Vitro Combination Index (CI) Scores for in Vitro

Activity against HER2+ BC Cell LinesActivity against HER2+ BC Cell Lines

Pegram et al. J Natl Cancer Inst. 2004;96:739.

SKSK--BRBR--33

BTBT--474474



Combination indexCombination indexDocetaxelDocetaxel PaclitaxelPaclitaxel

SKSK--BRBR--33

BTBT--474474



Combination indexCombination index

00 11 22 00 11 22

00 11 22 00 11 22 00 11 22

GemcitabineGemcitabine

Pivotal Combination Trial of FirstPivotal Combination Trial of First--Line Chemotherapy Line Chemotherapy ±±±±±±±± Trastuzumab Trastuzumab

in MBCin MBC

Adjuvant Adjuvant anthracyclineanthracycline

PaclitaxelPaclitaxel(n=96)(n=96)

Trastuzumab + Trastuzumab + paclitaxel (n=92)paclitaxel (n=92)

RR

HER2HER2

AC = doxorubicin 60 mg/mAC = doxorubicin 60 mg/m22 (or epirubicin 75 mg/m(or epirubicin 75 mg/m22) + cyclophosphamide 600 mg/m) + cyclophosphamide 600 mg/m22; q3w ; q3w ×××××××× 6. 6. Paclitaxel 175 mg/mPaclitaxel 175 mg/m22 q3w q3w ×××××××× 6. 6. Trastuzumab 4 mg/kg loading dose, then 2 mg/kg qw until progression.Trastuzumab 4 mg/kg loading dose, then 2 mg/kg qw until progression.

Slamon et al. N Engl J Med. 2001;344:783.

No adjuvant No adjuvant anthracyclineanthracycline

ACAC(n=138)(n=138)

Trastuzumab + AC Trastuzumab + AC (n=143)(n=143)

SS

RR

HER2HER2IHC 2+/3+IHC 2+/3+(N=469)(N=469)

50%

25.1

20.3

60

80

100

20

30


in MBC: Efficacyin MBC: Efficacy

Month

s (TTP, survival)

Month

s (TTP, survival)

ORR (%)

ORR (%)

Trastuzumab + chemotherapy (n=235)Trastuzumab + chemotherapy (n=235)

Chemotherapy (n=234)Chemotherapy (n=234)

50%

32%7.4

4.6

0

20

40

60

0

10

ORRORRPP<0.001<0.001

MedianMedianTTPTTP

PP<0.001<0.001

MedianMediansurvivalsurvivalPP=0.046=0.046

Month

s (TTP, survival)

Month

s (TTP, survival)

ORR (%)

ORR (%)

Slamon et al. N Engl J Med. 2001;344:783.Herceptin® (trastuzumab) PI.

0.60.6

0.80.8

1.01.0Trastuzumab + CT (n=235)Trastuzumab + CT (n=235)

Proportion alive

Proportion alive

CT (n=234)CT (n=234)


in MBC: Overall Survivalin MBC: Overall Survival

55 1515 2525 3535 4545

MonthsMonths

0.20.2

00

0.40.4

0.60.6

RR=0.80RR=0.80PP=0.046=0.046

Proportion alive

Proportion alive

20.3 mo20.3 mo(median)(median)

25.1 mo (median)25.1 mo (median)

Slamon et al. N Engl J Med. 2001;344:783.

22.1

18.4

60

80

100

20

30

Pivotal Combination Trial of FirstPivotal Combination Trial of First--LineLineChemotherapy Chemotherapy ±±±±±±±± Trastuzumab in MBC: Trastuzumab in MBC:

Paclitaxel Paclitaxel ±±±±±±±± Trastuzumab Subset EfficacyTrastuzumab Subset Efficacy

Trastuzumab + paclitaxel (n=92)Trastuzumab + paclitaxel (n=92)

Paclitaxel (n=96)Paclitaxel (n=96)

Month

s (TTP, survival)

Month

s (TTP, survival)

ORR (%)

ORR (%)

41%

17%6.9

3

0

20

40

60

0

10

ORRORRPP<0.001<0.001

MedianMedianTTPTTP

PP<0.001<0.001

MedianMediansurvivalsurvivalPP=0.17=0.17

Month

s (TTP, survival)

Month

s (TTP, survival)

ORR (%)

ORR (%)

Slamon et al. N Engl J Med. 2001;344:783.Herceptin® (trastuzumab) PI.

FirstFirst--Line Docetaxel Line Docetaxel ±±±±±±±±Trastuzumab in MBC: Schema of Trastuzumab in MBC: Schema of

Randomized Phase II TrialRandomized Phase II Trial

HER2HER2

DocetaxelDocetaxel100 mg/m100 mg/m22

q3w q3w ×××××××× 66

TrastuzumabTrastuzumab4 mg/kg, 4 mg/kg,

thenthen2 mg/kg qw 2 mg/kg qw

++

(n=92)(n=92)

Update of Extra et al. J Clin Oncol. 2005;23(16S):17s. Abstract 555. Marty et al. J Clin Oncol. 2005;23:4265.

OptionalOptionalcrossovercrossover

RRHER2HER2

IHC 3+/FISH+IHC 3+/FISH+(N=188)(N=188)

Both until Both until PDPD

DocetaxelDocetaxel100 mg/m100 mg/m22 q3w q3w ×××××××× 66

(n=90)(n=90)PDPD

TrastuzumabTrastuzumab(n=53)(n=53)

Randomized Phase II: FirstRandomized Phase II: First--line Trastuzumab + line Trastuzumab + Docetaxel Time to Disease Progression Docetaxel Time to Disease Progression

and Response Rateand Response RateEstimated probab

ility

Estimated probab

ility

1.01.0

0.80.8

0.60.6Trastuzumab (H) + Docetaxel (T)Trastuzumab (H) + Docetaxel (T)

Outcome Outcome (%)(%)

H + T H + T (n=92)(n=92)

T alone T alone (n=94)(n=94)

pp--valuevalue

ORRORR 6161 3434 0.0020.002

CRCR 77 22 ––

PRPR 5454 3232 ––

SDSD 2727 4444 ––

* p=0.0001* p=0.0001

Estimated probab

ility

Estimated probab

ility

0.40.4

0.20.2

0000 33 66 99 1212 1515 1818 2121 2424 2727 3030

MonthsMonths

Trastuzumab (H) + Docetaxel (T)Trastuzumab (H) + Docetaxel (T)

Docetaxel (T) aloneDocetaxel (T) alone

6.16.1

11.7*11.7*

IntentIntent--toto--treat population; response rates independently assessed.treat population; response rates independently assessed.

Marty, M. et al. J Clin Oncol; 23:4265-4274 2005

FirstFirst--Line Docetaxel Line Docetaxel ±±±±±±±±Trastuzumab in MBC: SurvivalTrastuzumab in MBC: Survival

Estimated

probab

ility

Estimated

probab

ility

Docetaxel + trastuzumabDocetaxel + trastuzumab

Docetaxel aloneDocetaxel alone

0.60.6

0.80.8

1.01.0

Marty et al. J Clin Oncol. 2005;23:4265.

PP=0.0325=0.0325

8.5 mo8.5 mo

00

0.20.2

Estimated

probab

ility

Estimated

probab

ility

0.40.4

00 55 1010 1515 2020 2525 3030 3535 4040 4545 5050MonthsMonths

31.231.222.722.7

FirstFirst--Line Docetaxel Line Docetaxel ±±±±±±±± Trastuzumab in Trastuzumab in MBC: Survival of Crossover PatientsMBC: Survival of Crossover Patients

0.60.6

0.80.8

1.01.0

Estimated

probab

ility

Estimated

probab

ility

Docetaxel + trastuzumab (n=92)Docetaxel + trastuzumab (n=92)

Docetaxel alone (n=41)Docetaxel alone (n=41)

Docetaxel alone/crossover toDocetaxel alone/crossover totrastuzumab (n=53)trastuzumab (n=53)

Marty et al. J Clin Oncol. 2005;23:4265.

Survival was longer with docetaxel and trastuzumab used concurrentlySurvival was longer with docetaxel and trastuzumab used concurrentlythan sequentially, although both strategies were effectivethan sequentially, although both strategies were effective

00 55 1010 1515 2020 2525 3030 3535 4040 5050454500

0.20.2

0.40.4

MonthsMonths

Estimated

probab

ility

Estimated

probab

ility

31.231.230.330.316.616.6

Trastuzumab and VinorelbineTrastuzumab and Vinorelbinein MBC: Phase II Trialsin MBC: Phase II Trials

TrialTrial nn

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

FirstFirst--lineline

Jahanzeb etJahanzeb et al,al, 2002 2002 3737 78 (6278 (62--90)90)

Bernardo et al, 2002 Bernardo et al, 2002 3232 84 (NR)84 (NR)

Jahanzeb et al. Oncologist. 2002;7:410; Bernardo et al. Ann Oncol. 2002;13(suppl 5):51. Abstract 181P; Burstein et al. J Clin Oncol. 2003;21:2889; Update of Chan et al. J Clin Oncol. 2005;23(16S):25s. Abstract 587; Burstein et al. J Clin Oncol. 2001;19:2722.

Bernardo et al, 2002 Bernardo et al, 2002 3232 84 (NR)84 (NR)

Burstein etBurstein et al, 2003 al, 2003 5454 68 (5468 (54--80)80)

Chan etChan et al, 2005 al, 2005 6565 61.5 (NR)61.5 (NR)

MultipleMultiple--line (1st line (1st -- 3rd)3rd)

Burstein et al, 2001 Burstein et al, 2001 4040 75 (5775 (57--89)89)

FirstFirst--Line Trastuzumab With Vinorelbine Line Trastuzumab With Vinorelbine or Taxane: TRAVIOTA Studyor Taxane: TRAVIOTA Study

•• Randomized comparison of trastuzumab (4 mg/kg loading, then Randomized comparison of trastuzumab (4 mg/kg loading, then 2 mg/kg qw) + either vinorelbine 25 mg/m2 mg/kg qw) + either vinorelbine 25 mg/m22 qw or taxane qw or taxane (paclitaxel 80 mg/m(paclitaxel 80 mg/m22, or docetaxel 35 mg/m, or docetaxel 35 mg/m22, qw), qw)•• Primary end point: ORRPrimary end point: ORR

•• EfficacyEfficacy•• Nonsignificant improvement in ORR with vinorelbine (n=41) Nonsignificant improvement in ORR with vinorelbine (n=41)

(51%; 95% CI, 35(51%; 95% CI, 35--67) vs taxane (n=40) (40%; 2567) vs taxane (n=40) (40%; 25--57), 57),

Update of Burstein et al. J Clin Oncol. 2006;24(18S):40s. Abstract 650.

•• Nonsignificant improvement in ORR with vinorelbine (n=41) Nonsignificant improvement in ORR with vinorelbine (n=41) (51%; 95% CI, 35(51%; 95% CI, 35--67) vs taxane (n=40) (40%; 2567) vs taxane (n=40) (40%; 25--57), 57), PP=0.37=0.37

•• SafetySafety•• Vinorelbine associated with more grade 3/4 hematologic Vinorelbine associated with more grade 3/4 hematologic

toxicity and dose delay for myelosuppressiontoxicity and dose delay for myelosuppression•• Other toxicities reflected known side effects of each CT Other toxicities reflected known side effects of each CT

agentagent•• Conclusion:Conclusion: at least comparable activity of vinorelbine at least comparable activity of vinorelbine

combination as taxane combinationscombination as taxane combinations

Trastuzumab qw + Trastuzumab qw + Docetaxel Docetaxel

100 mg/m100 mg/m22 q3wq3wUntil PDUntil PD

HERTAX Study DesignHERTAX Study Design

100 mg/m100 mg/m22 q3wq3w

Trastuzumab qwTrastuzumab qwDocetaxel Docetaxel

100 mg/m100 mg/m22 q3wq3w

RRHER2+ MBC,HER2+ MBC,

No previous CTNo previous CT(N=98)(N=98) PDPD

Bontenbal M, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1014)

Median time to first progressionMedian time to first progression

------ Combination therapy (DT)Combination therapy (DT)------ Monotherapy (T)Monotherapy (T)

Concurrent Concurrent vsvs Sequential Therapy With Sequential Therapy With DocetaxelDocetaxeland and TrastuzumabTrastuzumab in HER2+ MBCin HER2+ MBC

1.0

0

Overall SurvivalOverall Survival

0.0

00

.25

0.5

00

.75

1.0

0

0 6 12 18 24 30 36analysis time

time to progression 1

Combination T + DCombination T + D

Sequential T Sequential T →→→→→→→→ DD

Bontenbal M, et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1014)

0.0

00

.25

0.5

00

.75

0 6 12 18 24 30 36analysis time

months

Combination T + D: 30.5 moCombination T + D: 30.5 mo

Sequential T Sequential T →→→→→→→→ DD: 20.2 mo: 20.2 mo

analysis time

months

0.0

00.2

50.5

00.7

51.0

0

0 6 12 18 24 30 36analysis time

months

Progression Free SurvivalProgression Free Survival

Combination T + DCombination T + D

Sequential T Sequential T →→→→→→→→ DD

FrontFront--Line Trastuzumab for HER2+ Line Trastuzumab for HER2+ MBC: Sequence or Combination?MBC: Sequence or Combination?

ChemoRxChemoRx < < ChemoRxChemoRx + T + T ChemoRx < ChemoRx + T > TChemoRx < ChemoRx + T > T

National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology –

Breast Cancer. V.2.2008 (http://www.nccn.org)

Although singleAlthough single--agent agent trastuzumabtrastuzumab may be an may be an option for some patients, the combination of option for some patients, the combination of trastuzumabtrastuzumab and a and a taxanetaxane or or vinorelbinevinorelbineremains the standard of care for most remains the standard of care for most

patients with HER2+ metastatic breast cancerpatients with HER2+ metastatic breast cancer


Triplet Combinations of Triplet Combinations of Trastuzumab With Trastuzumab With ChemotherapyChemotherapy

Phase III Trial of FirstPhase III Trial of First--Line Trastuzumab Line Trastuzumab and Paclitaxel and Paclitaxel ±± Carboplatin (TCH) Carboplatin (TCH)

for MBCfor MBC

T qw T qw ×××××××× 18 +18 +P q3w P q3w ×××××××× 6 +6 +C q3w C q3w ×××××××× 6 6

T qw T qw ×××××××× 18 +18 +

T qw to PDT qw to PD

RR

HER2HER2IHC IHC 2+/3+2+/3+(N=196)(N=196)

TCH = TaxolTCH = Taxol®® (T; paclitaxel)(T; paclitaxel)--carboplatin (C)carboplatin (C)--HerceptinHerceptin®® (H; trastuzumab).(H; trastuzumab).

Robert et al. J Clin Oncol. 2006;24:2786.

T qw T qw ×××××××× 18 +18 +P q3w P q3w ×××××××× 66

End pointsEnd points

Primary: ORRPrimary: ORRSecondary: DOR, TTP, survival, Secondary: DOR, TTP, survival, safetysafety

T qw to PDT qw to PD

Dosing:Dosing: T 4 mg/kg wk 1, then 2 mg/kg qw; T 4 mg/kg wk 1, then 2 mg/kg qw; P 175 mg/mP 175 mg/m22; C AUC 6 ; C AUC 6

(N=196)(N=196)

Phase III Trial of FirstPhase III Trial of First--Line Line Trastuzumab and Paclitaxel Trastuzumab and Paclitaxel ±±

Carboplatin (TCH) in MBC: EfficacyCarboplatin (TCH) in MBC: Efficacy

52%

36%

35.732.2

30

40

50

60

ORR (%)

20

30

40

Month

s (PFS, O

S)

TCH (n=92)

TH (n=94)

All PatientsAll Patients

ORR = objective response rate.ORR = objective response rate.

Robert et al. J Clin Oncol. 2006;24:2786.

10.77.1

0

10

20

30

ORR (%) Median PFS (mo) Median OS (mo)

ORR (%)

0

10

20

Month

s (PFS, O

S)

PP=0.04=0.04 PP=0.03=0.03 PP=0.76=0.76

N983252: Randomized Phase II Trial of N983252: Randomized Phase II Trial of 2 Schedules of First2 Schedules of First--Line Paclitaxel + Line Paclitaxel +

Carboplatin + Trastuzumab (TCH) in MBCCarboplatin + Trastuzumab (TCH) in MBC

ARM A (q3w): TCHARM A (q3w): TCHRepeat q3w Repeat q3w ×××××××× 8 8

T (q3w) to PDT (q3w) to PD

RRHER2HER2


TCH = TCH = TaxolTaxol®® (T; paclitaxel)(T; paclitaxel)--carboplatin (C)carboplatin (C)--HerceptinHerceptin®® (H; trastuzumab). (H; trastuzumab).

Perez et al. Clin Breast Cancer. 2005;6:425.

ARM B (qw): TCHARM B (qw): TCHRepeat q4w Repeat q4w ×××××××× 6 6

T (qw) to PDT (qw) to PD

RR

ARM A dosing:ARM A dosing: P 200 mg/mP 200 mg/m22 + C AUC 6 q3w; T 4 mg/kg wk 1, then 2 + C AUC 6 q3w; T 4 mg/kg wk 1, then 2 mg/kg/wk during PC mg/kg/wk during PC →→→→→→→→ T T 8 mg/kg wk 1, then 6 mg/kg (q3w)8 mg/kg wk 1, then 6 mg/kg (q3w)

ARM B dosing:ARM B dosing: P 80 mg/mP 80 mg/m22 + C AUC 2 (wk 1+ C AUC 2 (wk 1--3); T 4 mg/kg wk 1, then 2 3); T 4 mg/kg wk 1, then 2 mg/kg qwmg/kg qw


TCH: Grade 3TCH: Grade 3--44Hematologic ToxicitiesHematologic Toxicities

% Incidence, Grade 3 (Grade 4)% Incidence, Grade 3 (Grade 4)

ToxicityToxicity q3w (n=43)q3w (n=43) qw (n=48)qw (n=48)

NeutropeniaNeutropenia 23 23 (70)(70) 42 42 (10)(10)

ThrombocytopeniaThrombocytopenia 30 30 (0)(0) 4 4 (0)(0)


ThrombocytopeniaThrombocytopenia 30 30 (0)(0) 4 4 (0)(0)

AnemiaAnemia 14 14 (2)(2) 66 (0)(0)

Febrile neutropeniaFebrile neutropenia 14 14 (2)(2) 2 2 (0)(0)

RBC transfusionsRBC transfusions 26 26 (0)(0) 6 6 (0)(0)

TCH: Grade 3TCH: Grade 3--44Nonhematologic ToxicitiesNonhematologic Toxicities

% Incidence, Grade 3 (Grade 4)% Incidence, Grade 3 (Grade 4)

ToxicityToxicity q3w (n=43)q3w (n=43) qw (n=48)qw (n=48)

NeurosensoryNeurosensory 21 21 (0)(0) 2 2 (0)(0)

MyalgiaMyalgia 14 14 (0)(0) 4 4 (0)(0)


MyalgiaMyalgia 14 14 (0)(0) 4 4 (0)(0)

ArthralgiaArthralgia 12 12 (0)(0) 88 (0)(0)

HypersensitivityHypersensitivity 5 5 (5)(5) 8 8 (0)(0)

FatigueFatigue 12 12 (0)(0) 17 17 (0)(0)

65

41

59

76

62

81

60

80

100

Percent

TCH: Efficacy Data for TCH: Efficacy Data for 2 Schedules2 Schedules

q3w (n=43)q3w (n=43)

qw (n=48)qw (n=48)

14

41

23

0

20

40

60

ORR CR 1-y PFS 2-y OS

Percent


••HER2+ MBCHER2+ MBC••ECOG PS ≤2ECOG PS ≤2

n=131n=131

N=263N=263

TrastuzumabTrastuzumab44--mg/kg loading dosemg/kg loading dose2 mg/kg qw thereafter 2 mg/kg qw thereafter

+ Doce+ Docetaxel taxel 100 mg/m100 mg/m22

q3wq3w

RRAANNDDOO

Phase III Study of Trastuzumab Phase III Study of Trastuzumab + Docetaxel + Docetaxel ±± Carboplatin Carboplatin in HER2+ in HER2+

Patients (Patients (BCIRG 007)BCIRG 007)

No crossoverNo crossover••ECOG PS ≤2ECOG PS ≤2••No prior chemo for No prior chemo for metastatic disease metastatic disease

n=132n=132

OOMMIIZZEE

Primary end point:Primary end point: TTPTTPSecondary end points:Secondary end points: ORR, toxicityORR, toxicity

TrastuzumabTrastuzumab4 mg/kg day 14 mg/kg day 12 mg/kg qw 2 mg/kg qw thereafterthereafter+ Doce+ Docetaxel taxel

75 mg/m75 mg/m22 day 2day 2q3wq3w

+ Carboplatin+ Carboplatin6 AUC day 26 AUC day 2

q3wq3w

Pegram et al. ASCO, 2007. Oral presentation and abstract LBA1008.

No crossoverNo crossover

% W

ithout progression

% W

ithout progression

100100

8080

6060

LogLog--rank rank PP=0.57=0.57

Trastuzumab + Docetaxel Trastuzumab + Docetaxel ±± Carboplatin Carboplatin in HER2+ Patients (in HER2+ Patients (BCIRG 007BCIRG 007): TTP): TTP

Trastuzumab + Docetaxel (n=131)Trastuzumab + Docetaxel (n=131) 99 99 11.111.1

Trastuzumab + Docetaxel + Trastuzumab + Docetaxel + 105105 10.310.3Carboplatin (n=132)Carboplatin (n=132)

Median TTP (mo)Median TTP (mo)EventsEvents

% W

ithout progression

% W

ithout progression

4040

2020

0011 22 33 4400

YearsYears

LogLog--rank rank PP=0.57=0.57

Forbes et al. ASCO, 2006. Oral Presentation and abstract LBA516.Pegram et al. ASCO, 2007. Oral presentation and abstract LBA1008.

Trastuzumab + Docetaxel Trastuzumab + Docetaxel ±± Carboplatin Carboplatin in HER2+ Patients (in HER2+ Patients (BCIRG 007BCIRG 007): OS): OS

0.6

0.8

1.0

Survival prob

ability

Survival prob

ability

Trastuzumab + Docetaxel (n=131)Trastuzumab + Docetaxel (n=131) 132 132 6767Trastuzumab + Docetaxel + Carboplatin Trastuzumab + Docetaxel + Carboplatin 132132 7171TotalTotal 263263 138138LogLog--rankrank PP=0.65=0.65

TreatmentTreatment No. of PatientsNo. of Patients EventsEvents


0

0.2

0.4

0 1 2 3 4 5

Median followMedian follow--up duration:up duration:Trastuzumab + Docetaxel : 39.1 mo vsTrastuzumab + Docetaxel : 39.1 mo vsTrastuzumab + Docetaxel + CarboplatinTrastuzumab + Docetaxel + Carboplatin : 39.2 mo: 39.2 mo

Trastuzumab + Docetaxel + CarboplatinTrastuzumab + Docetaxel + Carboplatin = 36.57 mo= 36.57 mo

Trastuzumab + Docetaxel = 36.40 moTrastuzumab + Docetaxel = 36.40 mo

Survival prob

ability

Survival prob

ability

YearsYears

Trastuzumab + Docetaxel Trastuzumab + Docetaxel ±± Carboplatin Carboplatin in HER2+ Patients (in HER2+ Patients (BCIRG 007BCIRG 007): ):

Grade 3/4 Hematologic AEsGrade 3/4 Hematologic AEs

% of Patients% of Patients

Trastuzumab +Trastuzumab +Docetaxel (n=131)Docetaxel (n=131)

Trastuzumab + Docetaxel + Trastuzumab + Docetaxel + Carboplatin (n=131)Carboplatin (n=131) PP ValueValue

Febrile neutropeniaFebrile neutropenia 12.212.2 1313

InfectionInfection 2929 22.922.9 0.3240.324InfectionInfection 2929 22.922.9 0.3240.324

Neutropenic infectionNeutropenic infection 16.816.8 9.29.2 0.0970.097

Septic deathSeptic death 00 1.51.5

AnemiaAnemia 5.35.3 10.710.7

ThrombocytopeniaThrombocytopenia 2.32.3 15.315.3 <0.001<0.001

AEs = adverse events.AEs = adverse events.


Trastuzumab + Docetaxel Trastuzumab + Docetaxel ±± Carboplatin Carboplatin in HER2+ Patients (in HER2+ Patients (BCIRG 007): BCIRG 007): Grade 3/4 Nonhematologic AEsGrade 3/4 Nonhematologic AEs

% of Patients% of Patients

Trastuzumab +Trastuzumab +Docetaxel (n=131)Docetaxel (n=131)

Trastuzumab + Docetaxel + Trastuzumab + Docetaxel + Carboplatin (n=131)Carboplatin (n=131) PP ValueValue

NeuropathyNeuropathy

SensorySensory 3.03.0 0.80.8 0.0480.048

MotorMotor 0.80.8 00 0.0680.068

ArthralgiaArthralgia 0.80.8 0.80.8 0.2520.252ArthralgiaArthralgia 0.80.8 0.80.8 0.2520.252

MyalgiaMyalgia 2.32.3 00 0.0410.041

Peripheral edemaPeripheral edema 3.83.8 1.51.5

DyspneaDyspnea 4.64.6 2.32.3

Rash/desquamationRash/desquamation 2.32.3 0.80.8 0.0020.002

NauseaNausea 00 3.83.8 <0.001<0.001

EmesisEmesis 1.51.5 3.03.0 0.00130.0013

LV dysfunctionLV dysfunction 0.80.8 00 0.010.01

LV = left ventricle.LV = left ventricle.



Trastuzumab Every 3 WeeksTrastuzumab Every 3 Weeks

Phase II TriaPhase II Triall of Paclitaxel + Trastuzumab of Paclitaxel + Trastuzumab q3w in MBC: Pharmacokineticsq3w in MBC: Pharmacokinetics

•• Comparison of serum trough concentrations (Comparison of serum trough concentrations (±±±±±±±± SE)SE) of trastuzumab q3w of trastuzumab q3w (with paclitaxel q3w) vs trastuzumab qw(with paclitaxel q3w) vs trastuzumab qw

Trastuzumab q3w (+ paclitaxel q3w)Trastuzumab q3w (+ paclitaxel q3w)Trastuzumab qwTrastuzumab qw

Serum

trough

Serum

trough

concentrations (

concentrations (µµg/mL)

g/mL)

8080

100100

120120

Q3w treatment cycles: trastuzumab 8 mg/kg loading, 6 mg/kg q3w; paclitaxel 175 mg/mQ3w treatment cycles: trastuzumab 8 mg/kg loading, 6 mg/kg q3w; paclitaxel 175 mg/m22 q3w.q3w.

Leyland-Jones et al. J Clin Oncol. 2003;21:3965.Cobleigh et al. J Clin Oncol. 1999;17:2639.

WeeksWeeks

Serum

trough

Serum

trough

concentrations (

concentrations (

6060

4040

2020

001010 2020 3030 4040 505000

•• Plasma trastuzumab trough levels are comparable for q3w and qwPlasma trastuzumab trough levels are comparable for q3w and qw


Trastuzumab beyond Trastuzumab beyond progressionprogression

Trastuzumab Treatment Beyond Progression in Trastuzumab Treatment Beyond Progression in Locally Advanced or MBCLocally Advanced or MBC

RANDOMIZATIONRANDOMIZATION

Capecitabine 2500 mg/mCapecitabine 2500 mg/m2 2

days 1 days 1 –– 14 q3w14 q3w

Trastuzumab 6 mg/kg q3wTrastuzumab 6 mg/kg q3w

Capecitabine 2500 mg/mCapecitabine 2500 mg/m22

days 1 days 1 –– 14 q3w14 q3w

Von Minckwitz G, et al. J Clin Oncol. 2009

TrastuzumabTrastuzumab Treatment Beyond Treatment Beyond Progression in Locally Advanced or MBCProgression in Locally Advanced or MBC


Safety and Efficacy ResultsSafety and Efficacy Results

Median followMedian follow--up up 15.6 months15.6 months

CapecitabineCapecitabinen = 78n = 78

CapecitabineCapecitabine + + TrastuzumabTrastuzumab

n = 78n = 78

HRHR PPValueValue

Primary EndpointPrimary Endpoint

TTP (Months)TTP (Months) 5.65.6 8.28.2 0.69 0.69 .03.03

Secondary EndpointSecondary EndpointSecondary EndpointSecondary Endpoint

OS (Months)OS (Months) 20.420.4 25.525.5 0.760.76 .13.13

Grade 3/4 Toxicity (%)Grade 3/4 Toxicity (%)

HandHand--Foot Foot Syndrome Diarrhea Syndrome Diarrhea

MucositisMucositis

2424

1919

33

3333

1616

22

Cardiac ToxicityCardiac Toxicity LVEF < 40% (n = 1), LVEF < 40% (n = 1), htnhtn (n = 2), MI (n = 1), pericardial (n = 2), MI (n = 1), pericardial effusion (n = 1), general cardiac complaint (n = 1)effusion (n = 1), general cardiac complaint (n = 1)


Phase III Study to Test if Total HER2+ Phase III Study to Test if Total HER2+ Blockade Improves Clinical OutcomeBlockade Improves Clinical Outcome

RRAANNDDOOMM

Lapatinib 1500 mg/day PO Lapatinib 1500 mg/day PO N=148N=148

Key InclusionKey Inclusion

•• HER2+(FISH+/ IHC3+) MBCHER2+(FISH+/ IHC3+) MBC

•• Progression onProgression on•• AnthracyclineAnthracycline

•• TaxaneTaxane

•• TrastuzumabTrastuzumabCrossover if PD Crossover if PD

after 4wk therapy after 4wk therapy MMIIZZAATTIIOONN

Lapatinib 1000 mg/day PO Lapatinib 1000 mg/day PO Trastuzumab 4 2 mg/kg IV Trastuzumab 4 2 mg/kg IV qw N=148qw N=148

Stratification FactorsStratification Factors

•• Visceral DiseaseVisceral Disease

•• Hormone Receptor Hormone Receptor

•• TrastuzumabTrastuzumab

•• Progression on most recent Progression on most recent trastuzumab regimentrastuzumab regimen

Crossover if PD Crossover if PD after 4wk therapy after 4wk therapy

(N=73)(N=73)

O’Shaughnessy et al. PASCO 2008

Patient and Tumor CharacteristicsPatient and Tumor Characteristics

Study ArmsStudy Arms

ITT PopulationITT Population

L L

N = 148N = 148

L+T L+T

N = 148N = 148

Median Age, Yrs. (range)Median Age, Yrs. (range) 51 (2951 (29--78)78) 52 (2652 (26--81)81)

% ECOG performance status 0/1/2% ECOG performance status 0/1/2 47/49/447/49/4 54/41/554/41/5

Median Prior Chemotherapy RegimensMedian Prior Chemotherapy Regimens 44 55Median Prior Chemotherapy RegimensMedian Prior Chemotherapy Regimens

%Patients ≥ 6 Prior Regimens%Patients ≥ 6 Prior Regimens

44

2828

55

3434

Median Prior Trastuzumab Regimens for MBCMedian Prior Trastuzumab Regimens for MBC 3 3 33

Median Time from Last Trastuzumab, daysMedian Time from Last Trastuzumab, days 2525 2727

# Patients # Patients HER2+ HER2+ 146146 147147

% ER and PgR Negative% ER and PgR Negative 5151 5151

% Visceral Disease% Visceral Disease 7474 7171


Treatment EfficacyTreatment Efficacy

LLN=145N=145

L + TL + TN=146N=146

Response Rate, %Response Rate, %**

(95% CI)(95% CI)

6.96.9

(3.4, 12.3)(3.4, 12.3)

10.310.3

(5.9, 16.4)(5.9, 16.4)

Odds Ratio (95% CI) Odds Ratio (95% CI) 1.5 (0.6,3.9)1.5 (0.6,3.9)

p=0.46p=0.46

*Confirmed CR+PR *Confirmed CR+PR ††CR+PR+SD ≥ 6 mo CR+PR+SD ≥ 6 mo

p=0.46p=0.46

Clinical Benefit Rate, %Clinical Benefit Rate, %††

(95% CI)(95% CI)

12.412.4

(7.5, 18.9)(7.5, 18.9)

24.724.7

(17.9, 32.5)(17.9, 32.5)

Odds Ratio (95% CI) Odds Ratio (95% CI) 2.2 (1.2, 4.5)2.2 (1.2, 4.5)

p=0.01p=0.01


Novel Growth Novel Growth Factor Directed Factor Directed

TherapiesTherapies

•• HER2 Monoclonal HER2 Monoclonal AntibodiesAntibodies•• TrastuzumabTrastuzumab•• PertuzumabPertuzumab

Esteva FJ and Hortobagyi GN. Sci Am 2008

•• PertuzumabPertuzumab•• TrastuzumabTrastuzumab--DM1DM1

•• HER2 TKIsHER2 TKIs•• LapatinibLapatinib•• HKIHKI--272272

•• HSP90 inhibitorsHSP90 inhibitors•• IGFIGF--IR IR MoAbMoAb & TKI& TKI•• PI3K inhibitorsPI3K inhibitors

Summary: Summary: AntiAnti--HER2 targeted therapyHER2 targeted therapy

•• HER2 remains an important therapeutic HER2 remains an important therapeutic target after progression on target after progression on trastuzumabtrastuzumab

•• Multiple lines of antiMultiple lines of anti--HER2 therapy are likely HER2 therapy are likely to improve longto improve long--term outcomesterm outcomesto improve longto improve long--term outcomesterm outcomes

•• The paradigm is not fundamentally different The paradigm is not fundamentally different from use of multiple antifrom use of multiple anti--estrogen or estrogen or chemotherapy agentschemotherapy agents

•• Novel approaches to HER2+ disease in the Novel approaches to HER2+ disease in the worksworks

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

[email protected]@mdanderson.org

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