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Breast Cancer 2014

S D MoodleyWits Donald Gordon Medical Centre

MBC milestones

Tamoxifen in MBC

1973

Ward. Br Med J 1973; 1: 13-14

Ward

60-77%Stable disease or response

Tamoxifen monotherapy

CMF in MBC

33%

3 months

Overall response rate

Median survival

1976

Canellos

Canellos et al. Cancer 1976; 38: 1882-1886

CMF vs L-phenylalanine mustard

C, cyclophosphamide;M, methotrexate;F, 5-fluorouracil

Paclitaxel in MBC

First publication: Nabholtz et al. Proc Am Soc Clin Oncol 1993; 12: abs 42

1993

CA139-048

29%

4.2 months

Paclitaxel monotherapy high vs low dose

Latest data (175 mg/m2 dose)

Nabholtz et al. J Clin Oncol 1996; 14: 1858-1867

Overall response rate

Time to progression

Aromatase inhibitors in MBC

4.2 months Median survival

First publication: Jonat et al. Proc Am Soc Clin Oncol 1995; 14: abs 130

Buzdar et al. Cancer 1998; 83: 1142-1152

Latest data

1995

Arimidex Study Group trials 3 and 4Anastrozole vs megestrol acetate

Docetaxel in MBC

14.5% Overall response rate

First publication: Chan et al. Proc Am Soc Clin Oncol 1997; 16: abs 540

1997

TAX 303Docetaxel vs doxorubicin

Nabholtz et al. J Clin Oncol 1999; 17: 1413-1424


Latest data

Docetaxel vs mitomycin C + vinblastineTAX 304

First publication: Nabholtz et al. Proc Am Soc Clin Oncol 1997; 16: abs 519

Latest data

Chan et al. J Clin Oncol 1999; 17: 2341-2354

Herceptin in MBC

First publication: Slamon et al. Proc Am Soc Clin Oncol 1998; 17: 98a, abs 377

1998

H0648gHerceptin + chemotherapy vs chemotherapy

7 months Median survival

Smith. Anticancer Drugs 2001; 12 (Suppl 4): S3-S10

Herceptin + paclitaxel vs paclitaxel (HER2 IHC 3+ )Latest data

32% Overall response rate

EBC milestones

Adjuvant CMF

21%

Risk of recurrence

Bonadonna et al. BMJ 2005; 330: 217

1976

The CMF programmeCMF vs observation

C, cyclophosphamide;M, methotrexate;F, 5-fluorouracil

First publication: Bonadonna et al. N Engl J Med 1976; 294: 405-410

Latest data

29%

Risk of death

1976

Adjuvant tamoxifen

36%

29%

Risk of recurrence

Risk of death

First publication: Lancet 1983; 1: 257-261

Br J Cancer 1988; 57: 608-611

Latest data

1983

NATO trialTamoxifen vs observation

Adjuvant anthracyclines

Risk of recurrence

First publication: Levine et al. J Clin Oncol 1998; 16: 2651-2658

Latest data

Levine et al. J Clin Oncol 2005; 23: 5166-5170

1998

NCIC MA.5CEF vs CMF

24%

C, cyclophosphamide; E, epirubicin;F, fluorouracil; M, methotrexate

Adjuvant taxanes

18%

Risk of recurrence

Risk of death

1998

First publication: Henderson et al. Proc Am Soc Clin Oncol 1998; 17: 101a, abs 390A

CALGB 9344AC→P vs AC

17%

A, doxorubicin;C, cyclophosphamide;P, paclitaxel

Latest data

Henderson et al. J Clin Oncol 2003; 21: 976-983

Adjuvant aromatase inhibitors

13% Risk of recurrence

First publication: Baum et al. Breast Cancer Res Treat 2001; 69: 210, abs 8

2001

ATACAnastrozole vs tamoxifen

Howell et al. Lancet 2005; 365: 60-62

Latest data

Adjuvant Herceptin

36%

34%

Risk of recurrence

Risk of death

First presentation: Piccart-Gebhart et al. ASCO 2005

Smith et al. Lancet 2007; 369: 29-36

Latest data

3 further large studies have also demonstrated similar significant reductions in risk of relapse and risk of death

Romond et al. N Engl J Med 2005; 353: 1673-1684; Slamon et al. SABCS 2006; abs 52

2005

HERA1-year Herceptin vs observation after chemotherapy

Herceptin landmarks

Defined as key studies in the evolution of Herceptin therapy

The data shown are from the most mature analyses available from these trials

Preclinical evidence for targeting HER2

Anti-HER2 monoclonal antibodies revert transformed cells to non-transformed phenotype

Drebin et al. Cell 1985; 41: 697-706

1985

HER2 amplified in 15 to 30% of breast cancers

Link between HER2 expression and breast cancer progression established

Slamon et al. Science 1987; 235: 177-182

1987

Herceptin + chemotherapy in MBC

First publication: Slamon et al. Proc Am Soc Clin Oncol 1998; 17: 98a, abs 377

1998

H0648gHerceptin + chemotherapy vs chemotherapy


Smith. Anticancer Drugs 2001; 12 (Suppl 4): S3-S10

Herceptin + paclitaxel vs paclitaxel (HER2 IHC 3+ )Latest data


First-line Herceptin monotherapy in MBC

2000

First publication: Vogel et al. Proc Am Soc Clin Oncol 2000; 19: 71a, abs 376

Vogel et al. Oncology 2001; 61 (Suppl 2): 37-42

Latest data



H0650g

Herceptin + docetaxel in MBC

First publication: Extra et al. Breast Cancer Res Treat 2003; 82: 47, abs 217

2003

M77001Herceptin + docetaxel vs docetaxel


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

Latest data


Herceptin + anastrozole in MBC

2.4 months Progression-free survival

Kaufman et al. Ann Oncol 2006; 17 (Suppl 9): LBA2

2006

TAnDEM

14.8% Clinical benefit rate

Herceptin + anastrozole vs anastrozole

Adjuvant Herceptin

36%

34%

Risk of recurrence

Risk of death

First presentation: Piccart-Gebhart et al. ASCO 2005

Smith et al. Lancet 2007; 369: 29-36

Latest data

3 further large studies have also demonstrated similar significant reductions in risk of relapse and risk of death

Romond et al. N Engl J Med 2005; 353: 1673-1684;Slamon et al. SABCS 2006; abs 52

2005

HERA1-year Herceptin vs observation after chemotherapy

Herceptin® (trastuzumab) for adjuvant therapy of HER2-positive early breast cancer (EBC)

Treatment guidelines for HER2-positive EBC

1. Goldhirsch et al 2011; 2. Aebi et al 2011; 3. www.nccn.org

Adjuvant therapy Recommended patient groups Administration

St. Gallen1

1 year of Herceptin®

(trastuzumab)

• HER2-positive tumours ≥1 cm

• HER2-positive node-negative tumours 0.51.0 cm (pT1b)

• Excludes: HER2-positive node-negative tumours 0.10.5 cm (pT1a)

• Preferred: concurrent use of Herceptin®

(trastuzumab) with chemotherapy

• Acceptable: chemotherapy followed by Herceptin® (trastuzumab) sequentially

ESMO2


(trastuzumab)

• HER2-positive tumours ≥1 cm

• Use of Herceptin® (trastuzumab) should be discussed with patients with small node-negative HER2-positive breast cancers

• Herceptin® (trastuzumab) may be started in parallel with a taxane

• Herceptin® (trastuzumab) should not be given concurrently with an anthracycline outside the context of a clinical trial

NCCN3


(trastuzumab)

• Category 1 recommendation: patients with HER2-positive tumours >1 cm

• Category 2A recommendation: patients with HER2-positive node-negative tumours 0.6‒1.0 cm

• HER2-positive node-negative pT1a or pT1b tumours: use of Herceptin® (trastuzumab) to be based on individual benefit:risk

• Preferred: doxorubicin and cyclophosphamide followed by concurrent administration of Herceptin® (trastuzumab) with taxane

• Preferred: docetaxel, carboplatin and Herceptin® (trastuzumab), other regimen see at NCCN

• Acceptable: chemotherapy followed by Herceptin® (trastuzumab) sequentially

Herceptin® (trastuzumab) recommended across international guidelines

Key Herceptin® (trastuzumab) studies in HER2-positive EBC

CT, chemotherapy (*selected from a list of approved regimens consisting of ≥4 cycles); RT, radiotherapy

1. Gianni et al 2011; 2. Slamon et al 2011; 3. Perez et al 2011

Study N Treatment armsFollow-up

(years)

HERA1 5102CT* ± RT observationCT* ± RT Herceptin® (trastuzumab) 1 year CT* ± RT Herceptin® (trastuzumab) 2 years

4

BCIRG0062 3222

AC docetaxelAC docetaxel+Herceptin® (trastuzumab) Herceptin®

(trastuzumab) Docetaxel+carboplatin+Herceptin® (trastuzumab) Herceptin® (trastuzumab)

5

NCCTG N98313 3505

AC paclitaxelAC paclitaxel Herceptin® (trastuzumab) AC paclitaxel+Herceptin® (trastuzumab) Herceptin®

(trastuzumab)

4

NSABP B-313 2101

AC paclitaxelAC paclitaxel+Herceptin® (trastuzumab) Herceptin®

(trastuzumab) 4

Extensive clinical programme involving >12,000 patients

HERA (BO16348)

HERceptin Adjuvant (HERA): a randomised three-arm multicentre comparison of 1

year and 2 years of Herceptin® (trastuzumab) versus

no Herceptin® (trastuzumab) in women with HER2-positive primary breast cancer

who have completed adjuvant chemotherapy

HERA: study design

*Stratification factors: nodal status, adjuvantCT regimen, hormone receptor status andendocrine therapy, age, region

Piccart-Gebhart et al 2005: Smith et al 2007; Gianni et al 2011

RANDOMISATION

Observation(n=1698)


(trastuzumab) 8 mg/kg6 mg/kg3-weekly schedule

(n=1703)

2 years of Herceptin®

(trastuzumab) 8 mg/kg6 mg/kg3-weekly schedule

(n=1701)

CROSSOVER

(n=885)

HER2-positiveinvasive EBC

(N=5102)*

Surgery + (neo)adjuvant

CT±RT

HERA: endpoints I

• Primary endpoint– Disease-free survival (DFS)

• Herceptin® (trastuzumab) 1 year vs observation• Herceptin® (trastuzumab) 2 years vs observation

• Secondary endpoints include:– Overall survival (OS) and cardiac safety

• Herceptin® (trastuzumab) 1 year vs observation• Herceptin® (trastuzumab) 2 years vs observation

– DFS, OS, RFS, DDFS, TTR, TTDR, cardiac safety, overall safety• Herceptin® for 1 year vs Herceptin® for 2 years

– Safety and tolerability of Herceptin®

– Cardiac dysfunction of Herceptin® vs observation

Piccart-Gebhart et al 2005: Smith et al 2007; Gianni et al 2011

HERA: disease-free survival at all time points

CI, confidence interval; HR, hazard ratio

1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011

1 year1

Medianfollow-up

2 years2

4 years3

Number of DFS eventsHerceptin® (trastuzumab)

vs observation

127 vs 220p<0.0001

218 vs 321p<0.0001

369 vs 458p<0.0001

0 1 2Favours

Herceptin®

(trastuzumab)

Favours noHerceptin®

(trastuzumab)

HR (95% CI)

DFS benefit

Consistent disease-free survival benefit for Herceptin® (trastuzumab) vs observation

HERA: overall survival at all time points

1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011

29 vs 37p=0.26

20051

1 year

59 vs 90p=0.0115

182 vs 213p=0.1087

20062

2 years

20083

4 years

Overall survival benefit for Herceptin® (trastuzumab) loses significance at 4 years due to extensive crossover

0 1 2Favours

Herceptin®

(trastuzumab) Favours

observation

HR (95% CI)

OS benefitMedian

follow-up No. of deaths

Herceptin® (trastuzumab)vs observation

HERA: adverse events and cardiac endpoints

*Crossover patients were censored from the date of starting Herceptin® (trastuzumab); †Not including cardiac death‡20 New York Heart Association II and 13 New York Heart Association III and IV§ Asymptomatic or mildly symptomatic Gianni et al 2011

Adverse event (AE), n (%)Observation*

(n=1719)

Herceptin®

(trastuzumab) 1 year (n=1677)

Patients with ≥1 Grade 3/4 AE 131 (8) 239 (14)

Patients with ≥1 SAE 129 (8) 199 (12)

Fatal AEs 6 (0) 12 (1)

Treatment withdrawals – 176 (11)

Cardiac endpoints

Cardiac death 1 (0) 0

Symptomatic CHF (II, III and IV)† 2 (0) 33 (2)‡

Confirmed significant LVEF drop§ 13 (1) 62 (4)

Herceptin® (trastuzumab) discontinued due to

cardiac problems– 87 (5)

Any type of cardiac endpoint 14 (1) 75 (5)

Low incidence of cardiac adverse events with Herceptin® (trastuzumab)

BCIRG 006

Multicentre Phase III randomised trial comparing doxorubicin and cyclophosphamide followed by

docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and Herceptin® (trastuzumab) (ACTH) and with

docetaxel, carboplatin and Herceptin®

(trastuzumab) (TCH) in the treatment of node-positive and high-risk node-negative adjuvant

patients

6 x T + C

ACT

AC TH

TCH

1 year of Herceptin® (trastuzumab)

HER2-positive

Node-positive or high-risk

node-negative EBC

N=3222

Stratified by nodes and hormone-receptor status

4 x AC 4 x T

1 year of Herceptin® (trastuzumab)

BCIRG 006: study design

AC: Doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q3w x 4T: Docetaxel 100 mg/m2 q3w x 4 (75 mg/m2 q3w x 6 when combined with carboplatin)C: Carboplatin AUC 6 q3w x 6 H: Herceptin® (trastuzumab) was administered weekly during chemotherapy (4 mg/kg loading dose, then

2 mg/kg qw), followed by 6 mg/kg q3w as monotherapy for a total treatment duration of 12 months

Slamon et al 2011

4 x AC 4 x T

BCIRG 006: end points and analyses

• Primary– Disease-free survival (DFS)

• Local/regional/distant recurrence

• 2nd primary invasivecancers

• Death due to any cause

• Secondary– Overall survival (OS)– Safety– Pathological and molecular

markers for predicting efficacy

1. Slamon et al 2005; 2. Slamon et al 2006; 3. Slamon et al 2011

1st interim efficacyanalysis after

322 DFS events (23 months)1

2nd interim efficacyanalysis after


3rd interim efficacyanalysis after


Aliv

e a

nd

dis

eas

e-f

ree

(%

)

BCIRG 006: disease-free survival at 5 years of follow-up

Slamon et al 2011

Years from randomisation

ACTH 84%TCH 81% ACT 75%

Significant disease-free survival benefit with Herceptin® (trastuzumab) in both regimens

0 1 2 3 4 65

20

40

60

80

100

0

n Events HR 95% CI p value

ACTH 1074 185 0.64 0.53‒0.78 <0.001

TCH 1075 214 0.75 0.63‒0.90 0.04

ACT 1073 257 1 (ref) − −

ACTH 92%TC H 91%ACT 87%

Years from randomisation

BCIRG 006: overall survival at 5 years of follow-up

Slamon et al 2011

Significant overall survival benefit with Herceptin® (trastuzumab) at long-term follow-up

n Events HR 95% CI p value

ACTH 1074 94 0.63 0.48‒0.81 <0.001

TCH 1075 113 0.77 0.60‒0.99 0.0038

ACT 1073 141 1 (ref) − −

BCIRG 006: summary of efficacy endpoints at 5-year follow-up

Slamon et al 2011

185 vs 257 0.64 (0.530.78)

No. eventsHerceptin®

(trastuzumab) vs observation

HR (95% CI)

214 vs 257 0.75 (0.630.90)

0.0 0.5 1.0 1.5

DFS

OS

ACTH

TCH

ACTH

TCH

94 vs 141 0.63 (0.480.81)

113 vs 141 0.77 (0.600.99)

HR (95% CI)

FavoursHerceptin® (trastuzumab)

Favoursobservation

Consistent efficacy benefit of Herceptin® (trastuzumab) withanthracycline-based and non-anthracycline-based regimens

BCIRG 006: Grade 3/4 non-haematological adverse events

*Statistically significantly fewer events

Events, %ACT

(n=1050)ACTH

(n=1068)TCH

(n=1056)

Arthralgia 3.2 3.3 1.4*

Myalgia 5.2 5.2 1.8*

Fatigue 7.0 7.2 7.2

Hand-foot syndrome 1.9 1.9 0.0*

Stomatitis 3.5 2.9 1.4*

Diarrhoea 3.0 5.6 5.4

Nausea 5.9 5.7 4.8

Vomiting 6.2 6.7 3.5*

Irregular menses 27.0 24.3 26.5

Low incidence of Grade 3/4 non-haematological AEsacross treatment groups at 5 years of follow-up

Slamon et al 2011

BCIRG 006: Grade 3/4 haematological adverse events

*Statistically significantly fewer events Slamon et al 2011

Similar incidence of Grade 3/4 haematological AEsacross treatment groups at 5 years of follow-up

Events, %ACT

(n=1050)ACTH

(n=1068)TCH

(n=1056)

Neutropenia 63.3 71.5 65.9*

Leucopaenia 51.8 60.3 48.2*

Febrile neutropenia 9.3 10.9 9.6

Neutropaenic infection 11.1 11.9 11.2

Anaemia 2.4 3.1* 5.8

Thrombocytopenia 1.6 2.1* 6.1

BCIRG 006: cardiac deaths and congestive heart failure (independently adjudicated)

Slamon et al 2009; Slamon et al 2011

p=0.0121 p<0.001

Stable CHF rates at long-term follow-up

Events, nACT

(n=1050)ACTH

(n=1068)TCH

(n=1056)

Cardiac-related death

First analysis (23 months) 0 0 0

Second analysis (36 months) 0 0 0

Third analysis (65 months) 0 0 0

Cardiac left ventricular function (CHF) Grade 3/4

First analysis (23 months) 3 17 4

Second analysis (36 months) 4 20 4

Third analysis (65 months) 7 21 4

NCCTG N9831 and NSABP B-31: combined analysis

NCCTG N9831: Phase III trial of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel with or without Herceptin® (trastuzumab) as adjuvant treatment

for women with HER2 overexpressing node-positive or high-risk node-negative breast cancer

NSABP B-31: A randomised trial comparing the safety and efficacy of adriamycin and cyclophosphamide followed by

paclitaxel (ACT) to that of adriamycin and cyclophosphamide followed by paclitaxel plus Herceptin®

(trastuzumab) (ACTH) in node-positive breast cancer patients who

have tumours that overexpress HER2

= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)

= T (paclitaxel 80 mg/m2/wk × 12)

= T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2 qw × 12)

= H (Herceptin® (trastuzumab) 4 mg/kg loading dose then 2 mg/kg qw × 52)

Combined analysis: study design

Perez et al 2011

Control group (n=2017): ACT

NCCTG N9831 Arm A (n=971)

NSABP B-31 Group 1 (n=1046)

Herceptin® (trastuzumab) group (n=2028): ACTH

NCCTG N9831 Arm C (n=973)

NSABP B-31 Group 2 (n=1055) T

H

ACT

T

H

ACT

AC

AC

Concurrent administration of Herceptin® (trastuzumab) with paclitaxel

Combined analysis: end points and analyses

• Primary– Disease-free survival

(DFS)• Local/regional/distant

recurrence• Contralateral breast

disease (including DCIS)• 2nd primary invasive

cancers• Death due to any cause

• Secondary– Overall survival (OS)– Time to distant

recurrence (TTDR)

1. Romond et al 2005; 2. Perez et al 2007; 3. Perez et al 2011

1st interim efficacyanalysis after

355 DFS events1

2nd interim efficacyanalysis after

619 DFS events2

3rd interim efficacyanalysis after

779 DFS events3

DCIS, ductal carcinoma in situ

Further analysis

• 102 women (5%) assigned to treatment arm did not receive trastuzumab because of cardiac symptoms or decrease in LV function. These patients were included in treatment arm in the ITT analysis.

• 413 women (20.4%) assigned to control arm received Trastuzumab after the first interim analysis reported positive findings in 2005. These patients were included in control arm in the ITT analysis.

Combined analysis: independent adjudication of cardiac events

Russell et al 2010AC, doxorubicin + cyclophosphamide; CHF, congestive heart failure; H, Herceptin® (trastuzumab); T, docetaxel.* Confirmed by ACREC Committee

Patients ACT(n=1755)

ACTH(n=1799)

Confirmed cardiacevents*, n (%)

8 (0.5) 36 (2.0)

Symptomatic CHF 7 (0.4) 34 (1.9)

Probable cardiac death 1 (0.1) 2 (0.1)

Hospitalised 5 (0.3) 11 (0.6)

Recovery 7 36

Incidence of symptomatic cardiac events with Herceptin® (trastuzumab)is very low at 2.0%, and most patients recover with treatment

NCCTG N9831: disease-free survival for sequential Herceptin® (trastuzumab)

*log-rank Perez et al 2011

ACTH

ACT71.8%

80.1%

Years fromrandomisation

Aliv

e a

nd

dis

eas

e-f

ree

(%

)

0

20

40

60

80

100

0 1 2 3 4 5 6735728

675643

624582

588530

539470

No.at risk

10971087

389330

Disease-free survival benefit observed with sequential treatment

n Events HR 95% CI p value*

1097 165 0.69 0.57−0.85 <0.001

1087 225

Years fromrandomisation

Aliv

e a

nd

dis

eas

e-f

ree

(%

)

0

20

40

60

80

100

0 1 2 3 4 5 6837830

790766

742707

691654

576519

No.at risk

949954

334288

NCCTG N9831: disease-free survival for sequential vs concurrent Herceptin® (trastuzumab)

*Significant p value pre-defined as p=0.00116 Perez et al 2011

Non-significant* disease-free survival benefit for concurrent treatment

84.4%

80.1%

ACTH

ACTH

n Events HR 95% CI p value*

949 139 0.77 0.53−1.11 0.022

954 174

Summary of clinical trials

Consistent disease-free survival benefit for Herceptin®

(trastuzumab) 1 year

1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3.Gianni et al 20114. Slamon et al 2011; 5. Romond et al 2005; 6. Perez et al 2011

1 0.543387

HERA13 2 0.643401

4 0.763401


Favoursobservation

10 2

BCIRG 0064

ACTHH vs ACTTCH vs ACT

50.75

0.643222

Study HRFollow-up (years)

N

Combined analysis5,6

NCCTG N9831/NSABP B-31)

2 0.483351

4 0.524045

HR (95% CI)

0.77

0.63

3401

3401

5 3222

10 2

Consistent overall survival benefit with adjuvant Herceptin® (trastuzumab)

1. Smith et al 2007; 2. Gianni et al 20113. Slamon et al 2011; 4. Perez et al 2011

2 0.66

4 0.85

4 4045 0.61

HR (95% CI)

Study HRFollow-up (years)

N

HERA1,2

BCIRG 0063

ACTHH vs ACTTCH vs ACT

Combined analysis4

NCCTG N9831/NSABP B-31)ACTHH


Favoursobservation

Low incidence of cardiac events across studies

*Cardiac events: CHF or cardiac death1. Rastogi et al 2007; 2. Perez et al 2008

3. Slamon et al 2011; 4. Procter et al 2010

NCCTG N9831 ACTH (n=570)2

BCIRG 006 ACTH (n=1068)3

BCIRG 006 TCH (n=1056)3

NCCTG N9831 ACTH (n=710)2

HERA CTH (n=1682)4

NSABP B-31 ACTH (n=947)1

3.3%

2%

0.4%

2.8%

0.8%

Time (years)

Cu

mu

lati

ve in

cid

en

ce (

%)

3.8%

0

2

4

6

8

10

0 1 2 3 4 5

Cumulative incidence of cardiac events* with 1 yearof Herceptin® (trastuzumab)remains low with long-term follow-up

Conclusions

• Disease-free survival and overall survival benefits with Herceptin® (trastuzumab) are maintained at long-term follow-up– Herceptin® (trastuzumab) may be administered

either concurrently or sequentially with chemotherapy, offering physicians different options to suit individual patient needs

• Herceptin® (trastuzumab) is well tolerated with a consistent safety and tolerability profile– Cumulative incidence of cardiac events remains

low after long-term follow-up

Gianni et al 2011; Perez et al 2011; Procter et al 2010; Russell et al 2010; Slamon et al 2011

Herceptin® (trastuzumab) for 1 year is the standard of carefor patients with HER2-positive EBC

PHARE* Trial results of subset

analysis comparing 6 to 12

months of trastuzumab in

adjuvant early breast cancerXavier Pivot, Gilles Romieu, Marc Debled, Jean-Yves Pierga, Pierre Kerbrat,

Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel Serin,Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie,Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David Khayat,Iris Pauporté, Andrew Kramar

*lighthouse in French

Protocol of

Herceptin®

Adjuvant with

Reduced

Exposure

NOAH (MO16432) data: Lancet 2010

NOAH (MO16432): Study design

H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2); T, paclitaxel (175 mg/m2)aA separate treatment group of HER2-negative patients received chemotherapy onlybHormone receptor-positive patients received adjuvant tamoxifen Gianni et al 2010

ATq3w x 3 cycles

Tq3w x 4 cycles

CMFq4w x 3 cycles

CMFq4w x 3 cycles

HER2-positive LABC(IHC 3+ or FISH-positive)

HER2-negative LABC(IHC 0/1+)a

ATq3w x 3 cycles

Tq3w x 4 cycles

Surgery followed by radiotherapyb

H + ATq3w x 3 cycles

H + T q3w x 4 cycles

H q3w x 4 cycles+ CMF q4w x 3 cycles

H continued q3wto week 52

(n=117) (n=118) (n=99)

19 crossed over to H

An international, open-label, Phase III study of neo-adjuvant−adjuvant Herceptin® (trastuzumab) in patients with

locally advanced or inflammatory HER2-positive breast cancer

NOAH: Inclusion criteria• Histologically proven locally advanced breast

cancer (T3N1/T4) or any T plus N2/N3, or any T plus involvement of ipsilateralsupraclavicular nodes

• HER2-positive disease was defined as IHC 3+ overexpression or HER2 amplification by FISH according to a central laboratory

– For the observational arm, HER2-negative disease was defined as IHC 0 or 1+ on the basis of local laboratory testing

• Mandatory hormone receptor assessment

• LVEF ≥55%Gianni et al 2010

NOAH: Endpoints

Primary endpoint

• Event-free survival (EFS) defined as:– Time from randomisation to disease recurrence or progression (local,

regional, distant or contralateral), or

– Death from any cause

Secondary endpoints

• Total pathological complete response in breast and axillary nodes (tpCR)

• Pathological complete response in breast tissue (bpCR)

• Overall clinical response rates (ORR)

• Overall survival (OS)

• Safety and tolerability, including cardiac safety

Gianni et al 2010

NOAH: Baseline characteristics

Gianni et al 2010

HER2-positive patients

Herceptin® (trastuzumab) + chemotherapy

(n=117)

Chemotherapy(n = 118)

Stage group, %

T4, non-inflammatory 42 43

Inflammatory disease 27 26

N2 or ipsilateral nodes 31 31

Hormone receptor status, %

ER- and/or PgR-positive 36 36

Both negative 64 64

Age group, %

<50 years 43 42

≥50 years 57 58

NOAH: EFS in the HER2-positive ITT

ITT, intent to treat Gianni et al 2010

With Herceptin® (trastuzumab)

Number at riskWith Herceptin®

(trastuzumab)Without Herceptin®

(trastuzumab)

Significant EFS benefit with the addition of Herceptin® (trastuzumab) to chemotherapy in HER2-positive patients

NOAH: EFS by subgroup in patients with HER2-positive disease

ER, oestrogen receptor; PR, progesterone receptor; cN, clinical nodal stage; bpCR, pathological complete response in breast tissue

HR (95% CI)

EFS benefit of Herceptin® (trastuzumab) is maintained across patient subgroups in HER2-positive patients

Gianni et al 2010

NOAH: Overall survival in the HER2-positive ITT population

ITT, intent to treat Gianni et al 2010

Trend towards overall survival benefit with the addition of Herceptin® (trastuzumab) to chemotherapy in HER2-positive patients

NOAH: pCR rates in the ITT population

ITT, intent to treatbpCR, pathological complete response in breast tissuetpCR, total pathological complete response (in breast and axillary nodes)* Absence of invasive tumour cells Gianni et al 2010

Significant improvement in pCR with addition of Herceptin® (trastuzumab) to chemotherapy in HER2-positive treatment groups

NOAH: Selected Grade 3/4 adverse events

H, Herceptin® (trastuzumab) Gianni et al 2010

HER2-positive HER2-negative

With H(n = 115)

Without H(n = 113)

Without H(n = 99)

n (%) n (%) n (%)

Febrile neutropenia 2 (2%) 2 (2%) 2 (2%)

Neutropenia 3 (3%) 5 (4%) 2 (2%)

Diarrhoea 1 (1%) 4 (4%) 1 (1%)

Stomatitis 1 (1%) 4 (4%) 3 (3%)

Infection 0 (0%) 0 (0%) 1 (1%)

Pneumonia 1 (1%) 0 (0%) 0 (0%)

Arthralgia 0 (0%) 3 (3%) 3 (3%)

Myalgia 1 (1%) 1 (1%) 1 (1%)

Peripheral neuropathy 1 (1%) 2 (2%) 0 (0%)

Low incidence of grade 3/4 adverse events with no difference between HER2-positive or negative patients

NOAH: LVEF during and after therapy

Gianni et al 2010

HER2-positive chemotherapyHER2-positive Herceptin®

(trastuzumab) + chemotherapy

20

40

60

80

LVEF

NOAH: Overview of safety and tolerability

• Herceptin® (trastuzumab) was well tolerated and adverse events were much the same in the three groups

• Safety and tolerability was consistent with the known profile of Herceptin® (trastuzumab)

• One patient in each arm had an adverse event that resulted in study drug discontinuation

• No increase in incidence of Grade 3 or 4 non-cardiac toxicities with the addition of Herceptin® (trastuzumab) to chemotherapy

• Low incidence of symptomatic cardiac dysfunction (1.7%), despite concurrent administration of Herceptin® (trastuzumab) with doxorubicin

Gianni et al 2010

NOAH: Conclusions

• Results from the NOAH study demonstrate the benefits of neo-adjuvant-adjuvant Herceptin®

(trastuzumab) as a treatment option for patients with HER2-positive LABC and with IBC– Neo-adjuvant Herceptin® (trastuzumab) with an

anthracycline- and taxane-containing chemotherapy significantly extends EFS in patients with HER2-positive disease

– The neo-adjuvant regimen with Herceptin® (trastuzumab) is well tolerated with acceptable cardiac safety

LABC, locally advanced breast cancerIBC, inflammatory breast cancerEFS, event-free survival Gianni et al 2010

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