HERCEPTIN Herceptin [trastuzumab] Foundation of care in women with HER2-positive breast cancer Update 2010 Herceptin Small Tumor Efficacy is consistent

HERCEPTIN

Herceptin [trastuzumab]Foundation of care in women with HER2-positive breast cancer Update

2010

Herceptin Small Tumor

Efficacy is consistent across tumor size and nodal status

Herceptin KIT MBC

Efficacy is consistent across tumor size and nodal status

Herceptin®(trastuzumab)

Foundation of care in women with HER2-positive breast cancer Update 2010

This document contains information outside of the indications of Herceptin

HER2: role in breast cancer

Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein and part of the HER family of 4 growth factor receptors (HER1/EGFR to HER4)

Overexpression of HER2 and / or amplification of the HER2 gene occurs in up to 15% of breast cancers

HER2 positivity is associated with • aggressive disease

• a high risk of relapse

• poor survival

Marla 2008Slamon 1989Slamon 1987

Penault-Llorca 2005

HER2 = Important therapeutic target

Spector 2009

5 mechanisms of action

t +Action 1 + + +t t t tAction 2 Action 3 Action 4 Action 5

Herceptin inhibits proliferation and induces apoptosis of HER2+ tumor cells

Spector 2009

EBC: Early Breast CancerMBC: Metastatic Breast Cancer

Herceptin : Expertise in all stages of Breast Cancer

Rela

pse

HERA

NSABP-B31

NCCTG N9831

BCIRG 006

FinHer

PACS-04

AdjuvantSurg

ery

TECHNONOAH

GeparQuintoNeoAltto

NeoSphere

Neoadjuvant

EBC

1st line

HO648g

M77001

BCIRG 007

CHAT

TAnDEM

RHEA

2nd+ lines

GBG-26

EGF 104900

Numerous Phase II studies

MBC

Pro

gre

ssio

n

Why do we give neoadjuvant therapy to patients with HER2-positive breast cancer?

• Decrease primary tumor size• Surgical removal of previously

inoperable tumor1

• Increase chance of breast-conserving surgery2,3

• Assess chemoresponsiveness of tumor4-6

• Predict outcome by assessment of tumor response5,7

• Decrease residual cancer burden8

• Improve long-term outcome4,8

• Reduce micrometastases4

1. van der Hage et al. 2007; 2. Fisher et al. 19983. van der Hage et al. 2001; 4. Connolly and Stearns 2010

5. von Minckwitz et al. 2008; 6. Kaufmnann et al. 20077. von Minckwitz et al. 2010; 8. Symanns et al. 2007

Judith Love

no standard length of treatment for neoadjuvant therapy hence 4, 6, and 8 cycles - vioce this inno label exists for neodajuvant therapy therefore there are no standards set regarding length of therapy, what chemo used, biologics - therefore these treatments are all off label although it is in guidelines for the chemo only PCR is not a recognised end point DFS is

Assessing response: pathological complete response as surrogate for survival (NSABP-B27)

• 2411 patients with primary operable breast cancer

• Primary endpoint: OS and DFS

• pCR was a significant predictor of OS, regardless of treatment (hazard ratio = 0.33; 95% CI: 0.23–0.47; P<0.0001)

Years after surgery7

Ove

rall

Surv

ival

(%) 100

40

pCR (n=410)

non-pCR (n=1889)

Bear et al. 2006

60

80

6543210

H + T q3w x 4 cycles

H q3w x 4 cycles+ CMF q4w x 3 cycles

H continued q3wto Week 52

Surgery followed by radiotherapy

NOAH: Study design

HER2-positive(IHC 3+ or FISH+)

HER2-negative(IHC 0/1+)

ATq3w x 3 cycles

Tq3w x 4 cycles

CMFq4w x 3 cycles

ATq3w x 3 cycles

Tq3w x 4 cycles

CMFq4w x 3 cycles

n=118 n=117 n=99


H + ATq3w x 3 cycles


Median follow-up = 3 years

H, trastuzumab (8 mg/kg loading dose then 6 mg/kg); AT, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2); q3w, every 3 weeks; T, paclitaxel (175 mg/m2); q4w, every 4 weeksCMF: Cyclophosphamide (600mg/m2), Methotrexate (40mg/m2), Fluorouracil (600mg/m2) Gianni 2010

NOAH: Herceptin almost doubles pCR rates

Median follow-up = 3 yearspCR = pathological Complete Response

0

10

20

30

40

50

WithoutHerceptin

WithHerceptin

Pati

ents

wit

h p

CR

, %

p=0.0007

43%

n=117n=118

22%

43%

Gianni 2010

NOAH: Herceptin extends event-free survival

Median follow-up = 3 yearsa Unadjusted for stratification variablesCTx: chemotherapy

1.00

0.75

0.50

0.25

0.000 6 12 18 24 30 36 42

Pro

babili

ty, event-

free s

urv

ival

Months

56 71 0.59 0.38-0.90 0.013

CTxHerceptin + CTx

118

117

n3-year

EFS (%) HR 95% CI p valuea

51 36

Events

Gianni 2010

NOAH : Herceptin is well tolerated with acceptable cardiac safety

Arthralgia

Diarrhea

Febrile neutropenia

Infection

LVEF decline

Myalgia

Neuropathy peripheral

Neutropenia

Pneumonia

Stomatitis

WithoutHerceptin

n=113

3

4

2

0

0

1

2

4

0

4

WithHerceptin

n=115

0

1

2

0

2

1

1

3

1

1

Selected grade ¾adverse events (%)

Gianni 2010

TECHNO Trial : PCR after NeoAdjuvant Chemotherapy predicts survival

Geparquinto : pCR with Herceptin is statistically better than with lapatinib.

60%

50%

40%

30%

20%

10%

0

50.4%

EC + Doc + lapatinib

EC + Doc + Herceptin

P<0.05

35.2%

Untch M, et al. SABCS 2010;#S3-1

(no invasive/ non-invasive residual in breast & nodes )

NeoSphere : pCR

Gianni L, et al. SABCS 2010;#S3-2

60%

50%

40%

30%

20%

10%

0

45.8

Herceptin + Doecetaxel

Herceptin + Pertuzumab +

Docetaxel

29,0

16.8%

Herceptin + Pertuzumab

% R

esp

onse

24.0%

Pertuzumab+ Docetaxel

NeoAltto StudyPathological Complete Response

Baselga J, et al. SABCS 2010;#S3-3

60%

50%

40%

30%

20%

10%

0

29.5%

lapatinib Herceptin

24.7

51.3%

Herceptin + lapatinib

% R

esp

onse


Rela

pse

HERA

NSABP-B31

NCCTG N9831

BCIRG 006

FinHer

PACS-04

AdjuvantSurg

ery

NOAH

MDACC

GeparQuattro


Neoadjuvant

EBC

1st line

HO648g

M77001

BCIRG 007

CHAT

TAnDEM

RHEA

2nd+ lines

GBG-26

EGF 104900


MBC

Pro

gre

ssio

n


Key trastuzumab studies in HER2-positive EBC

1. Gianni L, et al. 2011; 2. Slamon D, et al. 2009; 3. Perez EA, et al. 2011

Study N Treatment arms Follow-up(yrs)

HERA1 5102CT* ± RT observationCT* ± RT trastuzumab 1 year CT* ± RT trastuzumab 2 years

4

BCIRG0062 3222

AC docetaxelAC docetaxel+trastuzumab trastuzumabDocetaxel+carboplatin+trastuzumab trastuzumab

5

NCCTG N98313 2614

AC paclitaxelAC paclitaxel trastuzumabAC paclitaxel+trastuzumab trastuzumab

4

NSABP B-313 2043 AC paclitaxel

AC paclitaxel+trastuzumab trastuzumab 4

*Chemotherapy selected from a list of approved regimens consisting of ≥4 cycles

Extensive clinical programme involving >12,000 patients

Conclusions

• HERA

• Joint Analysis

• BCIRG-006

Pivotal adjuvant trials all now published

HERA (BO16348)

HERceptin Adjuvant (HERA): A randomised three-arm multicentre comparison of 1 year and 2 years of trastuzumab versus no trastuzumab in

women with HER2-positive primary breast cancer who have completed adjuvant chemotherapy

Surgery + (neo)adjuvant CTx ± RT

Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%

2 years Herceptin8 mg/kg 6 mg/kg3-weekly schedule

1 year Herceptin8 mg/kg 6 mg/kg3-weekly schedule

Women with locally determined HER2-positive invasive early breast cancer

HERA study design

After ASCO 2005, option of crossover

to Herceptin

Randomisation

Observation

≥

CTx: chemotherapyRT: radiotherapy Gianni 2009

HERA: Key inclusion criteria

• Histologically confirmed, completely excised, invasive breast cancer

• Centrally confirmed HER2 overexpression (IHC 3+) or amplification (FISH+)

• Node-positive or (sentinel) node-negative with >T1c

• Completed >4 cycles of approved adjuvant or neoadjuvant CT

• Baseline LVEF >55% (ECHO or MUGA scan) after completion of (neo)adjuvant CT and RT

• Known hormone receptor status

Piccart-Gebhart MJ, et al. 2005

HERA: Endpoints

Primary endpoint

• DFS

• Trastuzumab 1 year vs observation

• Trastuzumab 2 years vs observation

Secondary endpoints

• OS, TTR, TTDR, cardiac safety

• Trastuzumab 1 year vs observation

• Trastuzumab 2 years vs observation

• Trastuzumab 1 year vs trastuzumab 2 years

Gianni L, et al. 2011; Smith I, et al. 2007; Piccart-Gebhart MJ, et al. 2005

HERA: Cardiac safety endpoints

• Assessment of specific cardiac events• Severe CHF

• Symptomatic CHF

• Significant LVEF drop

• Confirmed significant LVEF drop

• Three interim analyses of cardiac endpoints after n=300, n=600 and n=900 patients treated/followed for 6 months

• Stopping guideline: ≥4% absolute increase in pre-defined cardiac events

Suter TM, et al. 2007

HERA: Study timeline

2005 2009 2010 2011

DFS data:• ASCO• NEJM1

*Event-driven analysis: 725 OS events required1. Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007;3. Gianni L, et al. 2011

2008

1st interimanalysis(n=475

DFS events)

2-year follow-up(n=539

DFS events)

2006

OS data:ASCO

4-year follow-up(n=827

DFS events)

4-year data:St Gallen

4-year data:Lancet Oncol3

OS data:Lancet2

2007 Q3/4 2012

Anticipatedrelease of

2-year data*

HERA: Patient characteristics (1)

Gianni L, et al. 2011

Patients, %

Observation(n=1698)

Trastuzumab 1 year(n=1703)

Age, years

<35 7 8

35−49 44 44

50−59 32 32

≥60 16 16

Prior (neo)adjuvant CT

No anthracyclines 6 6

Anthracyclines, no taxanes 68 68

Anthracyclines + taxanes 26 26

HERA: Patient characteristics (2)

*Status at randomisation

Patients, %

Observation(n=1698)

Trastuzumab 1 year(n=1703)

Menopausal status*

Premenopausal 14 15

Postmenopausal 45 45

Uncertain 41 40

Hormone receptor status

Negative 50 50

Positive 50 50

Nodal status

Neoadjuvant CT 10 11

Negative 33 32

13 29 29

≥4 28 28


Interim analysis and IDMC recommendations

As specified in the protocol, an interim analysis of 1-year vs 2-year Herceptin was performed in Q3 2008

The IDMC reviewed the interim analysis on 20 October 2008 and recommended that:

• no information on the 1-year vs 2-year Herceptin be released

• updated information on the 1-year Herceptin vs observation be presented and published

IDMC: Independent Data Monitoring Committee Gianni 2009

Surgery + (neo)adjuvant CTx ± RT

Centrally confirmed IHC 3+ or FISH+ and LVEF ≥ 55%

2 years Herceptin

8 mg/kg 6 mg/kg3-weekly schedule

1 year Herceptin

8 mg/kg 6 mg/kg3-weekly schedule

Women with locally determined HER2-positive invasive early breast cancer

HERA study design

After ASCO 2005, option of crossover

to Herceptin

Randomisation

Observation

CTx: chemotherapyRT: radiotherapy Gianni 2009

Sustained DFS Benefit

1414 1297

854 712

1352 1240

1280 1180

1020 992

1703 1698

1619 1564

1552 1440

1485 1363

No. at risk

100

80

60

40

20

0

0 6 12 18 24 30 4836 42

Months from randomisation

Events

369458

4-yearDFS

78.672.2

HR

0.76

1-year Herceptin

Observation+6.4%

Pati

ents

(%

)

95%Cl

0.66, 0.87

p value

<0.0001

+6.3%+8.4%

p<0.0001p<0.0001 p<0.0001

Gianni 2009Piccart 2005Smith 2007

HERA: DFS at all timepoints

1 year1

Medianfollow-up

2 years2

4 years3

Number of DFS events Trastuzumab

vs observation

127 vs 220P<0.0001

218 vs 321P<0.0001

369 vs 458P<0.0001

0 1 2Favourstrastuzumab

Favours notrastuzumab

HR (95% CI)

DFS benefit

1. Piccart-Gebhart MJ, et al. 2005; 2. Smith I, et al. 2007; 3. Gianni L, et al. 2011

Consistent DFS benefit for trastuzumab vs observation

HERA: Exploratory analysisof DFS by subgroup (1)

Smith I, et al. 2007

Consistent DFS benefit for trastuzumab across subgroups

Subgroup (number of patients)

Nodal status

Number of eventstrastuzumab vs

observationHR (95% CI)

Age at randomisation<35 years (253) 19 vs 31 0.57 (0.32‒1.01)35‒49 years (1508) 89 vs 150 0.54 (0.42‒0.70)

50‒59 years (1096) 71 vs 97 0.71 (0.52‒0.97)

≥60 years (544) 39 vs 43 0.91 (0.59‒1.41)

Menopausal status at randomisationPremenopausal (491) 43 vs 49 0.80 (0.53‒1.21)

Uncertain (1373) 70 vs 135 0.48 (0.36‒0.64)

Postmenopausal (1535) 105 vs 137 0.75 (0.58‒0.97)

Not assessed (372) 39 vs 50 0.66 (0.43‒1.00)

Negative (1099) 34 vs 58 0.59 (0.39‒0.91)

1‒3 positive nodes (976) 50 vs 80 0.61 (0.43‒0.87)≥4 positive nodes (953) 95 vs 132 0.64 (0.49‒0.83)

All patients (3401) 218 vs 321 0.64 (0.54‒0.76)

0.0 0.5 1.0 1.5HR

HERA: Exploratory analysisof DFS by subgroup (2)

Smith I, et al. 2007

Consistent DFS benefit for trastuzumab across subgroups

Subgroup (number of patients)

Pathological tumour size

Hormone receptor status

Previous radiotherapy

Type of (neo)adjuvant chemo

Number of eventstrastuzumab vs

observationHR (95% CI)

Any (neoadjuvant chemo) (372) 39 vs 50 0.66 (0.43‒1.00)0‒2 cm (1351) 61 vs 95 0.65 (0.47‒0.90)>2‒5 cm (1482) 97 vs 150 0.55 (0.43‒0.71)>5 cm (171) 20 vs 25 1.14 (0.63‒2.06)

ER-negative/PgR-negative (1627) 126 vs 190 0.63 (0.50‒0.78)ER-negative/PgR-positive (172) 12 vs 12 0.77 (0.34‒1.74)ER-positive/PgR-negative (460) 26 vs 39 0.82 (0.50‒1.34)ER-positive/PgR-positive (984) 46 vs 61 0.63 (0.43‒0.93)

Yes (2606) 183 vs 265 0.64 (0.53‒0.77)No (795) 35 vs 56 0.64 (0.42‒0.98)

No anthracyclines (202) 12 vs 15 0.76 (0.35‒1.62)Anthracyclines, no taxanes (2310) 132 vs 221 0.57 (0.46‒0.71)Anthracyclines and taxanes (889) 74 vs 85 0.80 (0.59‒1.10)

All patients (3401) 218 vs 321 0.64 (0.54‒0.76)

0.0 0.5 1.0 1.5

HR

0.6

0.5

0.4

0.3

0.2

0.0

0

1698 1557 1359 1040 722 432 194

0.1

Switched totrastuzumab

No.at risk

Pro

bab

ilit

y o

f cro

ssover

to t

rastu

zum

ab

885/1354 eligible patients (65%) crossed over to

trastuzumab

HERA: Patient crossoverto trastuzumab

6 12 18 24 30 36 42 48

1965

Time from randomisation (months)


Proportion of patients crossing over increased over time

HERA: DFS at 4 years, censored for crossover

100

80

60

40

20

00 6 12 18 24 30 4836 42

Months from randomisation

4-yearDFS

78.671.7

HR

0.69

95% CI

0.59–0.79

P value

<0.0001

Trastuzumab 1 year

Observation*6.9%

17031698

16191557

15521364

14851089

1414836

1352620

854234

1280448

1020324

No. at risk

Alive a

nd

dis

ease f

ree (

%)

*Excludes data from patients randomised to observation who crossed over to trastuzumab (n=885)Gianni L, et al. 2011

Censored analysis reinforces long-term DFS benefits

0 6 12 18 24 30 4836 42Months from randomisation

4-yearDFS

89.381.5

HR

0.53

95% CI

0.44–0.65

P value

<0.0001

7.8%

Trastuzumab 1 year

Observation*

100

80

60

40

20

0

17031698

16601635

16401524

16151287

15771047

1524827

953331

1447636

1149479

No. at risk

HERA: OS at 4 years, censoredfor crossover

Alive (

%)

Censored analysis suggests OS benefit of trastuzumab for 1 year

*Excludes data from patients randomised to observation who crossed over to trastuzumab (n=885)Gianni L, et al. 2011

HERA: Impact of crossover on DFS


Improvement in DFS even for late introduction of trastuzumab

100

80

60

40

20

0

0

Alive a

nd

dis

ease f

ree (

%)

6 12 18 24 30 36 42 48Months from randomisation

885 885 884 878 870 851 822 690 480

Selective crossover to trastuzumab

469 468 455 438 408 388 358 302 232

No crossover

No. at risk

HERA: Adverse events and cardiac endpoints

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

Adverse event, n (%)Observation*

(n=1719)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 adverse events 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)

Trastuzumab discontinued due tocardiac problems

87 (5)

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


Low incidence of cardiac adverse events with trastuzumab

HERA: Adverse event profilein crossover patients

*After 15 May 2005; †After crossover to trastuzumab; ‡Myocardial infarction and pulmonary embolism § Haemorrhagic stroke; **Not including cardiac death; ††Symptomatic or mildly symptomatic‡‡For 3 patients, LVEF drop happened soon after the release of trial results

Adverse event, n (%)No selective

crossover* (n=469)

Selective crossover†

(n=865)

Patients with ≥1 Grade 3/4 AE 19 (4) 80 (9)

Patients with ≥1 SAE 19 (4) 79 (9)

Fatal adverse events 2‡ (0) 1§ (0)

Treatment withdrawals 103 (12)

Cardiac endpoints

Cardiac death 0 0

Symptomatic CHF (II, III and IV) ** 1 (0) 9 (1)

Confirmed significant LVEF drop†† 5‡‡ (1) 26 (3)

Trastuzumab discontinued due to cardiac problems

43 (5)

Any type of cardiac endpoint 5 (1) 26 (3)


Crossover to trastuzumab does not affect tolerability

HERA: Risk of cardiac death, or severe or symptomatic CHF

Procter M, et al. 2010

Low incidence of cardiac events at long-term follow-up

0 6 12 18 24 30 36 42 48

0.05

0.10

0.15

Pro

bab

ilit

y o

f a c

ard

iac e

ven

t

Time (months)

ObservationTrastuzumab for 1 year

0

NCCTG N9831 and NSABP B-31

NCCTG N9831: Phase III trial of doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel with or without 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 trastuzumab (ACTH) in node-positive breast cancer patients who

have tumours that overexpress HER2

NCCTG N9831: Study design

Romond EH, et al. 2005

HER2-positiveEBC

N=2614

RANDOMISATION

AC (q3w x 4)

AC (q3w x 4)

AC (q3w x 4)

Paclitaxel(qw x 12)

Paclitaxel(qw x 12)

Trastuzumab(qw x 52)

Paclitaxel (qw x 12) + trastuzumab (qw x 52)

Arm A

Arm B

Arm C

Note: Sequential arm (B) was excluded from the joint analysis with NSABP B-31

n=819

n=981

n=814

AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4; Paclitaxel 80 mg/m2/wk × 12)Trastuzumab 4 mg/kg loading dose then 2 mg/kg qw × 52

NSABP B-31: Study design

Romond EH, et al. 2005

HER2-positiveEBC

N=2043

RANDOMISATION

AC (q3w x 4)

AC (q3w x 4)

Paclitaxel(q3w x 4 or

qw x 12)

Paclitaxel(q3w x 4 or qw x 12) + trastuzumab (qw x 52)

Group 1

Group 2

n=1024

n=1019

AC = doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4Paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2 qw × 12Trastuzumab 4 mg/kg loading dose then 2 mg/kg qw × 52

Combined analysis: Rationale

• Treatment arms broadly comparable• 52 weeks of trastuzumab added to anthracycline → paclitaxel

• Trastuzumab administered concurrently with paclitaxel for 12 weeks, then 40 weeks alone

• RT or hormonal therapy initiated after completionof 12-week regimen of trastuzumab + paclitaxel

• Joint efficacy analysis• Primary endpoint: DFS

• Secondary endpoint: OS

Perez EA, et al. 2007

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

Combined analysis: Study design


Control group (n=2017): ACT

NCCTG N9831 Arm A (n=971)

NSABP B-31 Group 1 (n=1046)

Trastuzumab group (n=2028): ACTH

NCCTG N9831 Arm C (n=973)

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

ACT

TH

ACT

AC

AC

Concurrent administration of trastuzumab with paclitaxel

Combined analysis: Key inclusion criteria

• Resected invasive HER2-positive breast cancer• NCCTG N9831: Node-positive; amended to allow high-risk

node-negative disease

• >1.0 cm if ER-negative or >2.0 cm if ER-positive

• NSABP B-31: Node-positive

• Adequate haematological, hepatic and renal function

• No significant sensory or motor neuropathy

• No significant past or active cardiac disease

• LVEF ≥ radiology facility’s lower limit of normal


Combined analysis: Endpoints and analyses

• Primary• DFS

• Local/regional/distant recurrence

• Contralateral breast disease (including DCIS)

• 2nd primary invasive cancers

• Death due to any cause

• Secondary• OS

• TTDR

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

1st interim efficacyanalysis after

355 DFS events1

2nd interim efficacyanalysis after

619 DFS events2

3rd interim efficacyanalysis after

779 DFS events3

NCCTG N9831 NSABP B-31

Patients, %ACT

n=971ACTHn=973

ACTn=1046

ACTHn=1055

Age, years <40

40495059≥6069

16.833.433.816.1

15.433.831.918.9

16.333.633.916.3

16.334.832.516.4

Tumour size, cm≤2.0 2.15.0≥5.0Not stated

40.452.47.10.1

38.053.68.40

40.350.47.61.7

38.050.110.61.3

Nodal involvement01349≥10

15.447.024.313.3

13.748.924.712.7

057.529.113.5

057.928.613.5

Tumour grade123Not stated

27.471.41.2

28.070.31.6

32.565.32.2

29.668.61.8

ER+ PgR+

51.439.4

49.737.9

52.340.3

52.038.9

Combined analysis: Patient characteristics (1)


Combined analysis: Patient characteristics (2)


NCCTG N9831 NSABP B-31

Patients, %ACT

n=971ACTHn=973

ACTn=1046

ACTHn=1055

Extent of surgeryMastectomyBreast conserving

60.539.4

62.038.0

60.038.9

60.738.7

PaclitaxelWeeklyEvery 3 weeks

100.00.0

100.00.0

16.183.9

16.183.9

RT Yes No Unknown

65.025.39.7

67.326.36.4

76.524.50.0

76.924.10.0

Hormonal therapy (First) Yes No Unknown

51.347.51.2

51.048.30.7

55.944.10.0

56.044.00.0

Combined analysis: DFS at 4 years of follow-up

Follow-up (years)

Alive a

nd

dis

ease-f

ree (

%)

3957021132188149589113001952 No.

at risk17561652

Stratified HR at 4 years = 0.52 (95% CI: 0.45‒0.60); P<0.001Factors: nodes, hormone receptor status, paclitaxel schedule, study

73.7%

86.8%

79.0%

85.7%

92.4%88.0%

ACT

ACTH

0

20

40

60

80

100

0 1 2 3 4 5Perez EA, et al. 2011

Significant DFS benefit of trastuzumab at all timepoints

Alive (

%)

Stratified HR at 4 years = 0.61 (95% CI: 0.50‒0.75); P<0.001Factors: nodes, hormone receptor status, paclitaxel schedule, study

85.6%96.1%

92.7%

93.0%95.1%97.7%

Combined analysis: OS at 4 years of follow-up

ACT

ACTH

Perez EA, et al. 2011 Follow-up (years)

0

20

40

60

80

100

0 1 2 3 4 5

5038861375196055497614201991 No.

at risk18751816

Significant OS benefit of trastuzumab at long-term follow-up

Combined analysis: Independent adjudication of cardiac events

Russell SD, et al. 2010

Confirmed cardiacevents, n (%)

ACT(n=1755)

ACTH(n=1799)

Total events 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 trastuzumabis very low at 2.0%, and most patients recover with treatment

NCCTG N9831: DFS with sequential trastuzumab

0

20

40

60

80

100

0 1 2 3 4Years from

randomisation735728

675643

624581

586529

95% CI

0.55−0.82

AC→T→H

AC→T

n

1097

1087

Events

164

222

5513447

71.9%79.7%

80.1%85.2%

No.at risk


Alive a

nd

dis

ease-f

ree (

%)

DFS benefit observed with sequential treatment

HR

0.67

P value

0.0005

10971087

NCCTG N9831: DFS for sequential vs concurrent trastuzumab

0

20

40

60

80

100

Alive a

nd

dis

ease-f

ree (

%)

0 1 2 3 4

Years fromrandomisation

837830

788766

740705

676641

5456418

No.at risk

*Significant P value pre-defined as P=0.00116

84.2%89.1%

79.8%85.7%


Non-significant* DFS benefit for concurrent treatment

AC→TH

AC→T→H

95% CI

0.60−0.94

n

949

954

Events

138

174

HR

0.75

P value*

0.0190

949954

NCCTG N9831 and NSABP B31: Conclusions

• In this analysis of more than 4000 patients, 1 year of trastuzumab provided a consistent long-term survival advantage after 4 years of follow-up• 48% relative reduction in DFS event rate

• 39% relative reduction in death rate

• Trastuzumab was associated with a low incidence of cardiac events, with no evidence of an increase over time

Trastuzumab for 1 year provides long-term benefits during concurrent or sequential administration with paclitaxel


BCIRG 006

Multicentre Phase III randomised trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) and with docetaxel, carboplatin and trastuzumab (TCH) in the treatment of node-positive

and high-risk node-negative adjuvant patients

6 x T + C

AC→T

AC→TH

TCH

1 year of 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 trastuzumab

BCIRG 006: Study design

4 x AC 4 x T

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: 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 D, et al. 2011

→

BCIRG 006: Key inclusion criteria

• Histologically confirmed breast cancer

• Definitive surgical treatment within 60 days of registration

• Stage T 1‒3, N0 or N1, M0

• 1/6 resected nodes positive for tumour

or

• 0/6 resected nodes positive for tumour and negative sentinel node biopsy AND at least one of the following risk factors

• Tumour size >2 cm

• ER and PgR negative

• Histologic and/or nuclear grade 23

• Age <35 years

• HER2-positive by FISH

• Age 1870 years

• Karnofsky performance status >80%

• No prior systemic therapy or RT for breast cancer


BCIRG 006: Endpoints and analyses

• Primary

• DFS

• Local/regional/distant recurrence

• 2nd primary invasivecancers

• Death due to any cause

• Secondary

• OS

• Safety

• Pathological and molecular markers for predicting efficacy

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

1st interim efficacyanalysis after

322 DFS events (23 months)1

2nd interim efficacyanalysis after


3rd interim efficacyanalysis after


BCIRG 006: Patient characteristics (1)


Patients, % AC→T(n=1073)

AC→TH(n=1074)

TCH(n=1075)

Age <50 years 52 52 54

Karnofsky performance status of 100 80 79 80

Mastectomy 59 63 60

RT 67 67 68

Hormonal therapy 49 50 50

BCIRG 006: Patient characteristics (2)

Patients, % AC→T(n=1073)

AC→TH(n=1074)

TCH(n=1075)

Number of positive nodes

0 29 28 29

13 38 38 39

410 22 24 23

>10 11 9 10

Tumour size, cm

≤2 41 38 40

>2 and ≤5 53 55 53

>5 6 7 6

ER+ and/or PgR+ 54 54 54


BCIRG 006: Patient crossover

• After the trastuzumab efficacy results were announced in April 2005, patients were permitted to cross over to receive trastuzumab

• 23/1073 patients (2.1%) randomised to AC→T crossed over to receive trastuzumab

• 1050/1073 patients (97.9%) remained in the AC→T arm for subsequent DFS, OS and safety comparisons


DFS: Median follow-up 5,4 years

1

0.9

0.8

0.7

0.6

0.5

0.4

0 12 24 36 48 60 72Time (months)

% a

live a

nd

Dis

ease-F

ree

AC-T100

AC-T100Herceptin

T75CbHerceptin

1073

1074

1075

Patients

257

185

214

Events

1 (reference)

0.64 (0.53 - 0.78)

0.75 (0.63 - 0.90)

HR (95% C.I.)

84%

81%

75%

<0.001

0.04

p

BCIRG006

Slamon 2009A: doxorubicin, 60 mg/m2; C: cyclophosphamide, 600 mg/m2; T100: docetaxel, 100 mg/m2 ; T75: docetaxel, 75 mg/m2 ; Cb: carboplatin AUC 6

Significant DFS benefit with trastuzumab in both regimens

BCIRG 006: OS at 5 years of follow-up

20

40

60

80

100

0 1 2 3 4 650

Alive (

%)

Years from randomisation


ACTHTCHACT

ACTHTCH ACT

n107410751073

Events94113141

HR0.630.77

1 (ref)

95% CI0.48‒0.810.60‒0.99

−

P value<0.0010.038

−

Significant OS benefit with trastuzumab at long-term follow-up

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

185 vs 257 0.64 (0.530.78)

No. eventsTrastuzumab

vs observation

HR (95% CI)

214 vs 257 0.75 (0.630.90)

0.0 0.5 1.0 1.5

DFS

OS

AC→TH

TCH

AC→TH

TCH

94 vs 141 0.63 (0.480.81)

113 vs 141 0.77 (0.600.99)

HR (95% CI)


Favours trastuzumab

Favours observation

Consistent efficacy benefit of trastuzumab withanthracycline-based and non-anthracycline-based regimens

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

*Statistically significantly fewer events

Events, % AC→Tn=1050

AC→THn=1068

TCHn=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 AEs across treatment groups at 5 years of follow-up

BCIRG 006: Grade 3/4 haematological adverse events

Events, % AC→Tn=1050

AC→THn=1068

TCHn=1056

Neutropenia 63.3 71.5 65.9*

Leucopenia 51.8 60.3 48.2*

Febrile neutropenia 9.3 10.9 9.6

Neutropenic infection 11.1 11.9 11.2

Anaemia 2.4 3.1* 5.8

Thrombocytopenia 1.6 2.1* 6.1


*Statistically significantly fewer events

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

BCIRG 006: Cardiac deaths and CHF (independently adjudicated)

Slamon D, et al. 2009; Slamon D, et al. 2011

Stable CHF rates at long-term follow-up

Events, n

AC→Tn=1050

AC→THn=1068

TCHn=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

P=0.0121 P<0.001

BCIRG 006: Mean LVEF (all observations)


LVEF >50% maintained long term in both Herceptin armswith good recovery of function in TCH arm

59

62

63

65

66

0 604858

2412

64

61

60

Time (months)

LVEF p

oin

ts (

%)

AC→T(n=1014)

AC→TH(n=1042)

TCH(n=1030)

36

BCIRG 006: Conclusions

• Trastuzumab for 1 year provides significant clinical benefits which are maintained over 5 years of follow-up

• Significant DFS and OS benefits maintained over the long-term

• Concurrent administration of trastuzumab with docetaxel was effective and well tolerated

• Consistent benefit of trastuzumab when used with either anthracycline-based or non-anthracycline-based chemotherapy

• Both combinations were well tolerated

• Lower incidence of adverse events (including cardiovascular) with non-anthracycline-based chemotherapy


Cardiac safety profile with trastuzumab is maintained with long-term follow-up

Time (years)

10

0

8

6

4

2

0

1 2 3 4 5Rastogi 2007

Perez 2008Slamon 2009Gianni 2009

Procter 2010

Cum

ula

tive inci

dence

Congest

ive h

eart

failu

re

(Gr3

/4)

and c

ard

iac

death

(%

) Anthracycline-containing

Anthracycline-free

B-31 AC THerceptin (n=947)

N9831 AC THerceptin (n=570)

BCIRG 006 AC THerceptin (n=1068)

N9831 AC T Herceptin (n=710)

HERA CTx Herceptin (n=1682)

BCIRG 006 TCbHerceptin (n=1056)

3.8%3.3%2.8%

2%

0.8%0.4%

A: doxorubicin, 60 mg/m2; C: cyclophosphamide, 600 mg/m2; T100: docetaxel, 100 mg/m2 ; T75: docetaxel, 75 mg/m2 ; Cb: carboplatin AUC 6

1-year Herceptin increasesDisease Free Survival

N9831

HERA

N9831/B31

BCIRG006

2184

3401

3401

3387

3968

2147

DFS benefit

0.67

0.76

0.64

0.54

0.48

0.64

0.0005

<0.0001

<0.0001

<0.0001

<0.00001

<0.001

Median

Follow-up

(years)

5.5

4

2

1

2.9

5.41

HR

2Favours

no Herceptin

Trials n

AC T H

CTx H

AC TH H

AC TH H

Treatment P

0 Favours

Herceptin

Risk of Relapse is reduced by up to 52%Perez 2008; Gianni 2009; Smith 2007;

Piccart 2005; Perez 2007; Slamon 2009

1-year Herceptin extends OverallSurvival in Early Breast Cancer

N9831

HERA

N9831/B31

BCIRG006

2184

3401

3401

3968

2147

OS benefit

0.281

0.1087

0.0115

0.0007

<0.001

Median

Follow-up

(years)

5.5

4

2

2.9

5.4

1

HR

Risk of Death is reduced by up to 37%

Trials n

AC T H

CTx H

AC TH H

AC TH H

Treatment P

2Favours

no Herceptin

0.86

0.85

0.66

0.65

0.63

Confounded by crossover

Confounded by crossover

0 Favours

Herceptin

Perez 2009 ; Gianni 2009; Smith 2007;Piccart 2005; Perez 2007; Slamon 2009

Adjuvant Herceptin is changing the epidemiology of the disease

20.000

18.000

16.000

14.000

12.000

10.000

8.000

6.000

4.000

2.000

0

2000 2005 2010 2015 2020

27.727

Num

ber

of

pati

ents

wit

h

MB

C in 5

EU

countr

ies

Projected MBC patients

Impact of Herceptin

Weisgerber-Kriegl 2008

Herceptin therapy is unilaterally recommended for HER2-positive disease

NCCNconsider Herceptin for

Node- & 0.6-1cmHormone receptor-

ESMOuse Herceptin for

St Gallenuse Herceptin for

≥ 1cm

OR

Node+

NCCN 2010; Kataja 2009; Goldhirsch 2009

≥ 1cm

OR

Node+

use Herceptin for

Node- & 0.6-1cmHormone receptor-

(if grade>1 & unfavorable features)

>1cm

Node+

OR

OR

Conclusions

• 1-year adjuvant Herceptin extends Overall Survival

• Herceptin delivers high cure rates for womenwith HER2-positive early breast cancer

• Herceptin is well tolerated with acceptable cardiac safety

• Herceptin is the foundation of care in women with HER2-positive early breast cancer

De Vita 2006Smith 2007

Romond 2005Marty 2005

Spector 2009Procter 2010


Rela

pse

HERA

NSABP-B31

NCCTG N9831

BCIRG 006

FinHer

PACS-04

AdjuvantSurg

ery

NOAH

MDACC

GeparQuattro


Neoadjuvant

EBC

1st line

HO648g

M77001

BCIRG 007

CHAT

TAnDEM

RHEA

2nd+ lines

GBG-26

EGF 104900


MBC

Pro

gre

ssio

n


Study design

Anthracycline+

Cyclophosphamide

n=138

Anthracycline+

Cyclophosphamide+

Herceptin

n=143

Paclitaxel175mg/m2

n=96

Paclitaxel175mg/m2

+Herceptin

2 mg/kg/week(4mg/kg loading dose)

n=92

HER2-positive MBC

(IHC 2+ or IHC 3+)

No prior chemotherapy for

MBC

H0648g

Slamon 2001

Study design

a Additional cycles of docetaxel administered at investigator’s discretion. Patients progressing on docetaxel alone could cross over to receive Herceptin

b 2 patients did not receive study medicationFISH, fluorescence in situ hybridisation; LVEF, left ventricular ejection fraction

Docetaxel 100 mg/m2

q3w x 6 cycles +Herceptin 4 mg/kg loading dose,

then 2 mg/kg qw until disease progression

n=92b

HER2-positive MBC (IHC 3+ and / or FISH+)

No prior chemotherapy for MBCBaseline LVEF>50%

n=188

Docetaxel 100 mg/m2

q3w x 6 cycles

n=94a

M77001

Marty 2005

Study design

Anastrozole1mg/day

+Herceptin

2 mg/kg/week(4mg/kg loading

dose)n=103

Postmenopaused women

with HER2-positive

(ICH 3+ or FISH+)

& hormone receptor-positive

(ERpositive and/or PgR

positive) MBC

Anastrozole1mg/day

n=104

Kaufman 2009

TAnDEM

1st line Herceptin increasesProgression Free Survival

Month

s

14

12

10

8

6

4

2

0

11.7 months(TTP)

6.9 months(TTP)

4.8 months(PFS)+5.6 months

p=0.0001

+3.9 monthsp<0.001 +2.4 months

p=0.0016

pacl

itaxe

lpa

clita

xel

+

Her

cept

in

doce

taxe

ldo

ceta

xel

+

Her

cept

in

anas

troz

ole

anas

troz

ole

+ H

erce

ptin

n=188H0648g

n=186M77001

n=207TAnDEM

Slamon 2001Marty 2005

Kaufman 2009

1st line Herceptin extends Overall Survival

* Subgroup analysis limited to 188 patients (total population = 469)** 70% of patients in the anastrozole alone arm crossed over to receive Herceptin after progression on anastrozole alone

Month

s35

30

25

20

15

10

5

0

31.2 months

22.1 months

28.5 months

+8.5 monthsp=0.0325

+3.7 monthsp=0.17%*

+4.6 monthsp=0.325**

n=188H0648g

n=186M77001

n=207TAnDEM

pacl

itaxe

lpa

clita

xel

+

Her

cept

in

doce

taxe

ldo

ceta

xel

+

Her

cept

in

anas

troz

ole

anas

troz

ole

+ H

erce

ptin


Kaufman 2009

Herceptin in MBC considerably improves the prognosis of HER2-positive disease

HER2 positive, Herceptin (n=191)

HER2 negative (n=1782)

HER2 positive, no Herceptin (n=118)

100

80

60

40

20

00 12 24 36 48 60

Months from diagnosis

Pro

babili

ty o

f su

rviv

al (%

)

Dawood 2010


Rela

pse

HERA

NSABP-B31

NCCTG N9831

BCIRG 006

FinHer

PACS-04

AdjuvantSurg

ery

NOAH

MDACC

GeparQuattro


Neoadjuvant

EBC

1st line

HO648g

M77001

BCIRG 007

CHAT

TAnDEM

RHEA

2nd+ lines

GBG-26

EGF 104900


MBC

Pro

gre

ssio

n

EBC: early breast cancer MBC: metastatic breast cancer

Progression under Herceptin-based 1st line therapya (monotherapy or with taxane- or with non taxane-chemotherapy)

GBG-26 is the 1st randomised Phase III study to investigate continuation of Herceptin beyond progression

Xeloda 1,250 mg/m2

bid d1-14 q21d +

continuation of Herceptin 6 mg/kg q3w

n=78

Xeloda 1,250 mg/m2 bid d1-14 q21d

n=78

RANDOMIZATION

a Includes 3 patients who received adjuvant Herceptin + taxane von Minckwitz 2009

Continuation of Herceptin improves response rate

CR: Complete ResponsePR: Partial ResponseCBR: CR+PR or SD > 24 weeks

Herceptin + Xeloda (n=75)

Xeloda (n=68)

48

Pati

ents

(%

)

0

10

20

30

40

50

60

70

80

CR + PR CBR

Median follow-up 15.6 months

p=0.01

27

75

54

p=0.007

von Minckwitz 2009

Continuation of Herceptin prolongs median Time to Progression

400

0.0

0.2

1.0

0.8

0.6

0.4

10 20 30

8.25.6

Pro

babili

ty HR=0.69 (p=0.034)

Xeloda (n=78)Herceptin + Xeloda (n=78)

Time from 1st progression (months)Median follow-up 15.6 months

von Minckwitz 2009

Continuation of Herceptin extendsOverall Survival

HR=0.76 (p=0.26)

20.4

400

0.0

0.2

1.0

0.8

0.6

0.4

10 20 30

25.5

Xeloda (n=78)Herceptin + Xeloda (n=78)

Pro

babili

ty

Time from 1st progression (months)Median follow-up 15.6 months

von Minckwitz 2009

Continuation of Herceptin beyond progression was not associated with increased toxicity

* includes hand-foot syndrome

AnemiaCardiovascular disorderDiarrheaDyspneaEdema FatigueFebrile neutropeniaFeverInfectionMucositisNail changesNeutropeniaSensory neuropathySkin changes*ThrombocytopeniaVomiting

Herceptin + XelodaXelodaGrade ¾ adverse events (%)

05.2

15.62.60

3.92.61.32.61.33.95.32.6

32.50

1.3

2.782.7

18.96.81.45.400

8.12.70

4.45.4

24.31.394.1

von Minckwitz 2009

EGF104900 study: Lapatinib ± Herceptin in progressing MBC

Crossover if Progressive Disease

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

n=296

Lapatinib 1500 mg qd

n=148

Lapatinib 1000 mg qd+ Herceptin 4 2 mg/kg qw

n=148

Blackwell 2009Blackwell 2010

Heavily pretreated population

Lapatinib

n=148

Lapatinib + Herceptin

n=148

Median prior chemotherapy regimens

% patients ≥ 6 prior regimens

Median prior Herceptin regimens for MBC

4

28

3

5

34

3

Study Arms

ITT Population


Herceptin + lapatinib is superior to lapatinib alone

PFS, progression-free survivalOS, overall survival

Lapatinib + Herceptin n = 146

Lapatinib n = 145

ORR, overall response rateCBR, clinical benefit rate

12.4

(%)

(weeks

)

p=0.46

p=0.01

p=0.008

p=0.026

0

5

10

15

20

25

30

ORR CBR0

10

20

30

40

50

60

PFS OS

6.9

10.312.4

24.7

8.112.0

40.9

60.2


Study Arms

ITT Population

Cardiac & safety events

Total # patients with event1

Grade 3/4

Serious events2

Event related to study drug(s)

Fatal3

1 Two patients experienced 2 events (other event was Grade 1/2) 2 Serious events defined as LV dysfunction ≥ Grade 3 or LVEF decrease ≥ 20% relative to baseline + below institutions LLN3 Cardiac failure; cause of death: pulmonary thromboembolism

Lapatinib

n=146


n=149

3

1

3

2

0

111

3

10

10

1


Adverse events All grades (% patients)

Anorexia

Cough

Dermatitis acneiform

Diarrhea

Dyspnea

Fatigue

Headache

Nausea

Rash

Vomiting

Lapatinib

n=146

10

10

10

48

10

19

9

28

29

18


n=149

11

5

5

60

12

21

10

28

22

14

adverse event(incidence ≥ 10%)


Herceptin given in 2nd line or beyondincreases Progression Free Survival

* HR = 0.69; 95% Cl, 0.48 to 0.97; p = 0.0338** HR = 0.73; 95% Cl, 0.57 to 0.93; p = 0.008

8.2 months(TTP)

+2.6 monthsp=0.0338*

2.7 months(PFS)

+0.9 monthsp=0.008**

0

Month

s

Xelo

daXe

loda

+ H

erce

ptin

n=156GBG-26

1

2

3

4

5

6

7

8

9

lapa

tnib

lapa

tinib

+ H

erce

ptin

n=291EGF104900

Von Minckwitz 2009Blackwell 2009Blackwell 2010

Herceptin given in 2nd line or beyondextends Overall Survival

* HR = 0.76; two-sided; p = 0.257** HR = 0.74; 95% Cl, 0.57 to 0.97; p = 0.026

Month

s

25.5 months

+5.1 monthsp=0.257* 14 months

+4.5 monthsp=0.026**

0

5

10

15

20

25

30

Xelo

daXe

loda

+ H

erce

ptin

n=156GBG-26

lapa

tnib

lapa

tinib

+ H

erce

ptin

n=296EGF104900

Von Minckwitz 2009Blackwell 2009Blackwell 2010

Conclusions

• Herceptin improves Overall Survival in 1st line MBC

• Benefit of continuing Herceptin beyond progression has been confirmed in phase III trial

• Herceptin is well tolerated with an acceptable cardiac safety profile

• Herceptin is the foundation of any treatment regimen in HER2-positive breast cancer


Kaufman 2009von Minckwitz 2009


Update on CNS metastases in HER2-positive breast cancer

Prevention

Delay

Overall Survival increase

Quality of Life

Herceptin given in 1st Line MBC delays the occurrence of CNS metastases

13.1

2.1

p=0.0008

19

7

P<0.001

02

4

6

8

10

12

14

16

18

20

Not treatedwith Herceptin

n=80

Treatedwith Herceptinn=100


n=11

Treatedwith Herceptinn=38

Media

n t

ime t

o C

NS m

eta

stase

s (m

onth

s)

Dawood 2008Park 2009

Herceptin delays the progression of CNS metastases

2.9

p=0.006

7.8

01

2

3

4

5

6

7

8

9

10


n=11

Treatedwith Herceptin

after BMn=29

Media

n T

TP o

f in

tracr

ania

l tu

mors

(m

onth

s)

Park 2009

Brain radiotherapy makes blood-brain barrier more permeable

Herc

epti

n in

cere

bro

spin

al fluid

(ng/m

L)

0

100

200

300

400

Beforeradiotherapy

226ng/ml

Afterradiotherapy

After radiotherapy for brain metastases,Herceptin levels in brain (n = 6)

Stemmler 2007

Disruption of the blood-brain barrier occurs at thesite of brain metastases

MRI

HER2-positive brain lesion revealed by 89 Zr-Herceptin PET imaging and confirmed by MRI

PET

Dijkers 2010

Herceptin: the only anti-HER2 treatment improving Overall Survival of patients with CNS metastases

11.9 months

Month

s (0

S)

+Her

cept

in*

Churchn=26

25

20

15

10

5

0

+Her

cept

in**

+Her

cept

in**

*

+Her

cept

in*

Bartschn=38

Dawoodn=254

Parkn=40

+8.9 monthsp=0.05

21 months

11.6 months13.6 months

+12 monthsp<0.001

+5.5 monthsp=0.03

+8.1 monthsp<0.001

* After BM

** After WBRT

*** Before or at time of BM diagnosis

Church 2008Bartsch 2007Dawood 2008

Park 2009

Anti-HER2 targeted therapy:the future…

Pertuzumab and trastuzumab bind to different regions on HER2 and have synergistic activity

● Preferentially inhibits ligand-independent HER2 signalling

● Prevents shedding of HER2 ECD● Flags cells for destruction by the

immune system

● Inhibits HER2 forming dimer pairs● Suppresses multiple HER signalling

pathways, leading to a more comprehensive blockade of HER signalling

● Flags cells for destruction by the immune system

Subdomain IV of HER2

HER2 receptor

Trastuzumab Pertuzumab

Dimerisation domain

of HER2

Baselga 2009

BO17929: a Phase II trial of pertuzumab + trastuzumab in HER2-positive MBC patients progressing during trastuzumab-based therapy

Pertuzumab + trastuzumab

Coh

ort

s

1 a

nd

2

HER2-positive MBC progressing on trastuzumab +

chemotherapy (n=29)

16 patients receivedpertuzumab

+ trastuzumab

Coh

ort

3 Pertuzumab

PD

HER2-positive MBC progressing on trastuzumab

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

Primary objective: efficacy (ORR and/or SD> 6 months)

Secondary objectives:• safety profile of the combination, duration of response, time to response, TTP,

PFS (evaluate safety of combined antibody treatment)• efficacy (response rate + stabilisation of disease = CBR)

Heavily pretreated population• median 3 prior lines of therapy in the metastatic setting

MBC: Metastatic Breast CancerCBR: Clinical Benefit Rate

Baselga 2010Baselga 2009

Pertuzumab / trastuzumab combination therapy more active than treatment with either agent alone

a: only 27 patients evaluable: 1 patient did not progress on pertuzumab monotherapy before moving onto combination therapy and 1 patient’s tumour was unassessable after cycle 2b: n=14 as at data cut-off, 1 patient had not reached overall best response end point (8 cycles of assessment during this phase) and 1 patient died before efficacy assessmentP, pertuzumab monotherapy; P + T, pertuzumab / trastuzumab combination therapy;CR: Complete Response; PR: Partial Response; ORR: Overall Response Rate; SD: Stable Disease; PD: Progressive Disease

CR, %

PR, %

ORR, %

SD ≥ 6 months, %

CBR, %

(CR + PR + SD ≥ 6

months)

PD, %

Cohorts 1 and 2

(P + T) n=66

7.6

16.7

24.2

25.8

50.0

50.0

Cohort 3 (P)

n=27a

0.0

3.4

3.4

6.9

10.3

not available

Cohort 3 (P P + T)

n=14b

0.0

21.4

21.4

21.4

42.8

57.1

Baselga 2010Baselga 2009

Pertuzumab / trastuzumab combination safety profile comparable to pertuzumab monotherapy

AEs: Adverse Events

AEs

Asthenia

Back pain

Chills

Diarrhoea

Fatigue

Nausea

Rash

Vomiting

Weight decrease

BO17929 Cohort 3 Pertuzumab monotherapy

n=29

BO17929 Cohort 3 Pertuzumab + trastuzumab

n=16Any grade, %

17

17

0

48

17

34

10

24

0

Grade 3/4, %

0

0

0

3

3

0

0

0

0

Any grade, %

13

13

19

31

25

31

19

25

19

Grade 3/4, %

0

6

0

6

6

0

0

0

0

Baselga 2009

BO17929: pertuzumab + trastuzumab has a similar cardiac safety profile to trastuzumab

• No significant changes in LVEF over the treatment period

Only 3 patients in the trial had a decrease in LVEF of ≥10% points and <50% absolute value but all were asymptomatic

• No additional cardiac safety signals were observed

LVEF: Left Ventricular Ejection FractionBaselga 2010Baselga 2009

CLEOPATRA: a Phase III trial of trastuzumab + pertuzumab in the 1st line setting

An international, Phase III, randomised, double-blind, placebo-controlled study (~250 sites worldwide)• End points

• PFS and OS• (cardiac) Safety

1:1 HER2-positiveMBC (n=800a)

Docetaxel + trastuzumab + pertuzumab

Docetaxel + trastuzumab + placebo

1:1

www.clinicaltrials.gov

PHEREXA: a Phase II trial of trastuzumab + capecitabine with or without pertuzumab

aRecruitment started Jan 2010

An international, Phase II, randomised study in patients with HER2-positive MBC that has progressed after 1st line of trastuzumab-based therapy in the metastatic setting

1:1 HER2-positiveMBC (n=450a)

Trastuzumab + capecitabine+ pertuzumab

Trastuzumab + capecitabine

1:1


T-DM1: 1st-in-class HER2 antibody-drug conjugate (ADC)

Monoclonal antibody: trastuzumab

Target expression: HER2

Highly potent chemotherapy(maytansine derivative)

Cytotoxic agent: DM1

Systemically stableBreaks down in target cancer cell

LinkerT-DM1

Baselga 2009

T-DM1 selectively delivers a highly toxic payload to HER2-positive tumour cells

T-DM1 binds to the HER2 protein on cancer cells

Baselga 2009


Receptor-T-DM1 complex is internalised into HER2-positive cancer cell

Baselga 2009


Potent antimicrotubule agent is released once inside the HER2-positivetumour cell

Baselga 2009

Single-agent T-DM1 Phase II studies in pretreated HER2-positive MBC

Phase II (TDM4258g)

n=112

• Single-arm study of single-agent T-DM1 (3.6 mg/kg iv q3w) • HER2-positive MBC patients who have progressed on HER2 therapy • Previously received trastuzumab and ≥ 1 line of chemotherapy for MBC

Phase II (TDM4374g)

n=110

• Single-arm study of single-agent T-DM1 (3.6 mg/kg i.v. q3w) for HER2-positive MBC patients who have been pretreated with lapatinib, trastuzumab, capecitabine, anthracyclines and taxanes

• Two HER2-directed regimens in the metastatic setting• PD on last regimen received

Vogel 2009Krop 2009Krop 2009

TDM4258g: encouraging efficacy demonstrated for single-agent T-DM1

Population

All efficacy evaluable patients

112

38.4

25.0

4.9

n

ORR, %

Investigator assessed

Independent review

PFS, months

After 9.5 months’ follow-

up

Lapatinib pretreated

patients

67

35.8

23.9

na

Patients with centrally confirmed

HER2-positive disease

75

48

32.0

na

Heavily pretreated population• median 3 prior chemotherapy agents in the metastatic setting

na: not available Vogel 2009

TDM4374g: a Phase II trial of T-DM1 in HER2-positive MBC patients progressing during HER2-targeted therapy

T-DM13.6 mg/kg

q3w

• Patients with HER2-positive MBC (n=110)• Prior exposure to anthracycline, taxane, capecitabine,

lapatinib and trastuzumab (median 7 prior agents of therapy in the metastatic setting)

• PD on last regimen received

Krop 2009

Substantial clinical benefit seen with T-DM1 in a heavily pretreated population

aIncluding unconfirmed PRsCI, confidence interval; n/a, not assessed

Independent reviewn=110

32.7(24.1, 42.1)

032.746.418.21.80.9

44.5 (35.1, 54.3)7.3 (0-11.7)

Investigator assessedn=110

30.0(22.0, 39.4)

1.828.252.713.60.92.7

40.0 (31.1, 49.3)

n/a

Tumour response

ORR, %(95% CI) CR PR SDa

PD Unevaluable Missing CBR, % (95% CI)Median PFS, months (range)

Krop 2009

T-DM1 is well tolerated with no new safety signals observed

AST: aspartate aminotransferase

Only 6 (5.5%) patients discontinued due to AEs

AST increased

Constipation

Dry mouth

Fatigue

Headache

Nausea

Pyrexia

Thrombocytopenia

Grade 1, %

11

17

17

30

17

26

13

11

Grade 2, %

11

3

4

26

3

10

8

13

Grade 3, %

3

1

0

3

0

1

1

4

Grade 4, %

0

0

0

0

0

0

0

2

All grades, %

25

21

20

59

20

37

22

29

Krop 2009

T-DM1: potential future clinical benefit for heavily pretreated patients with HER2-positive MBC

T-DM1 has shown robust single-agent activity in heavily pretreated patient groups

•substantial clinical benefit observed in patients with PD during prior HER2-targeted therapy

T-DM1 is well tolerated with no dose-limiting cardiac events observed

Further investigation of T-DM1 is ongoing

Krop 2009

EMILIA: ongoing Phase III study of T-DM1 vs capecitabine + lapatinib in the 2nd-line setting

HER2-positive incurable locally advanced breast cancer or MBC

Prior trastuzumab and taxanen=580

T-DM1 3.6 mg/kg q3w

Capecitabine + lapatinib

n=221 as of 16 March 2010

1:1


TDM4450g: ongoing Phase II study of T-DM1 vs trastuzumab + docetaxel in 1st-line HER2-positive MBC

HER2-positive locally advanced or MBCNo prior chemotherapy for metastatic disease

n=120

T-DM1 Trastuzumab + docetaxel

● Study start date July 2008● Fully recruited www.clinicaltrials.gov

TDM4788g / BO22589: Phase III study of T-DM1 + pertuzumab vs trastuzumab + docetaxel in 1st-line HER2-positive MBC

HER2-positive locally advanced or MBCNo prior chemotherapy for metastatic disease

n=1092

T-DM1 + placebo Trastuzumab + docetaxel

T-DM1 + pertuzumab


Summary: pertuzumab and T-DM1 are promising new therapeutic agents for HER2-positive MBCPertuzumab

• 1st HER2 dimerisation inhibitor

• Has demonstrated encouraging clinical efficacy and tolerability in combination with trastuzumab

• Offers a more comprehensive approach to blocking HER2-driven signalling than trastuzumab alone

T-DM1

• 1st HER2-directed ADC delivering cytotoxic drug specifically to HER2-positive tumour cells while retaining the biological activity of trastuzumab

• Has demonstrated encouraging clinical efficacy and tolerability in heavily pretreated patients

Clinical trials of both agents are ongoing, including pertuzumab and T-DM1 in combination

Outlook

• Small or Node negative HER2 positive tumors : should you botHER?

HER2-positive cancers have a distinct biology and an aggressive behaviour

• Do we have a cure?

18 Infusions of Herceptin deliver high cure rates for women with HER2-positive early breast cancer

• Is Herceptin efficient at all HER2 positive tumors?

Herceptin efficacy is consistent across tumor size and nodal status

• What do the international guidelines recommend?

St Gallen 2011 guidelines recommend : Herceptin when tumor size >0,5 cm

HER2-positive cancers have a distinct biology and an aggressive behaviour(1,5)

1 Oakman at al;Annals of oncology 21, 2010 (Supplement 7);vii112-vii119

2 Gonzalez-Angulo et al. J Clin Oncol 2009;27;5700-5706

3 Chia et al, Journal of Clinical Oncology, 2008, p5697-5704

4 Tovey et al, British Journal of Cancer, 2009,1-4

5 Banerjee et al, Lancet Oncol 2010; 11: 1193–99

Small HER2-positive tumors have a high risk of relapse(1)

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 50

Reccu

rren

ce-F

ree S

urv

ival

[pro

posit

ion

]

Time since diagnosis (years)

93,7%

HER2-negative

n=965T1a,bN0MO tumors

P<0,0001

HER2-negative


0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 50

Reccu

rren

ce-F

ree S

urv

ival

[pro

posit

ion

]

Time since diagnosis (years)

93,7%

HER2-negative

n=965T1a,bN0MO tumors

P<0,0001

HER2-negative

77,1%

HER2-positive

HER2-positive


Finnish population based study(2)

20

40

60

80

100

0 1 2 3 4 50

Dis

tan

t D

isease-F

ree S

urv

ival

Years of folluw-up

CISH HER2-negative (n=167)

1-10 mmn Node negative

P<0,0001

HER2-negative

CISH HER2-positive (n=17)

HER2-positive

Joensuu(2)

Small tumors were defined in these studies as tumors of 1 cm or less(1,2)

Breast Cancer Classification(3)*

T1mi : Tumor ≤ 1 mm

T1a : Tumor >1mm but ≤ 5mm

T1b : Tumor >5mm but ≤ 10 mm

T1c : Tumor > 10 mm but ≤ 20 mm

T2 : Tumor > 20 mm but ≤ 50 mm

T3 : Tumor > 50 mm

T4 : Tumor of any size with direct extension to

the

chest wall and/or the skin

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 100

Bre

ast

Can

cer-

Sp

ecifi

c S

urv

ival

(pro

bab

ilit

y)

Time (years)

CISH HER2-negative (n=167)

n=1420

P<0,001

HER2-negative

Chia*(1)

Even for node negative patients, HER2 positivity doubles the 10-year risk of dying from breas cancer

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 100

Bre

ast

Can

cer-

Sp

ecifi

c S

urv

ival

(pro

bab

ilit

y)

Time (years)

HER2-negative

n=1420

P<0,001

HER2-negative

HER2-positive

HER2-positive

Chia*(1)

Even for node negative patients, HER2 positivity doubles the 10-year risk of dying from breas cancer

0.2

0.4

0.6

0.8

1.0

0 2 4 6 8 100

Bre

ast

Can

cer-

Sp

ecifi

c S

urv

ival

Follow-up (years)

HER2-negative (n=240)

P<0,001

HER2-negative

HER2-positive (n=22)

HER2-positive

Tovey(2)

Poor survival outcomes in HER2-positive breast cancer patients with low-grade, node-negative tumours(2)

1 3 5 7 9

Outlook









40

50

60

70

80

90

0 1 2 3 4Time

(years)

ACTHACT

5

87%

92%

BCIRG 006

% A

live

ACT + Herceptin (n=1.074)

ACT (n=1.073)

HR=0,63 (95%CI,0.48_- 0.81)

P<0.001

100 ___

6

Herceptin significantly improves Overall Survival Relatives reduction in the risk of death of 37%

0

20

40

60

80

100

0 1 2 3 4

Follow-up

(years)

AC-TH

AC-T

5

Joint analysis of N9831 and NSABP B31 trials

Alive a

nd

dis

ease-f

ree (

%)

ACT-T+ Herceptin

AC-T

HR* adj=0,48 (95%CI,0.41_- 0.57)

P<0.001

6

Over 85% of women live without disease progression 4 years after the start of adjuvant treatment with Herceptin(3)

Number at risk

AC-TH (n=1.989)

AC-T (n=1.979)

*Nodes, receptor status, paclitaxel schedule, protocol

73.1%77.6%

86.4%

92.3%87.9%

85.9%

1.854

1.800

1.347

1.235

868

753

522

460

202

168

4

8

Outlook









Combined analysis of N9831/B31 and N981 trials, 4 year FU(2)

Combined analysis of N9831/B31 and N981 trials, 4 year FU(2)

Disease Free Survival Rate

Adjuvant Herceptin decreases the recurrence or death rate* for patient with small tumors ≤1cm

Adjuvant Herceptin significantly improves DFS for patients with small tumors ≤1cm(1)

HERA: Disease Free Survival at 2 year median follow-up(2)

Herceptin overall survival benefit for node negative tumors is confirmed after a median follow-up of more than 5 years

Adjuvant Herceptin plus Chemotherapy results in consistent benefits for node-negative patients(1)

Outlook









Documents

HERCEPTIN Herceptin [trastuzumab] Foundation of care in women with HER2-positive breast cancer Update 2010 Herceptin Small Tumor Efficacy is consistent