Herceptin® in the adjuvant setting

Herceptin® in the adjuvant setting: rationale

HER2 overexpression is an early event in breast cancerdevelopment and is associated with aggressive disease

Herceptin® offers

A new mechanism of antitumour activity

Proven clinical benefits in the metastatic setting,including increased survival when used in combination with chemotherapy

Greater benefit when used earlier in metastatic disease

A favourable safety profile and good tolerability

Four major ongoing Herceptin® adjuvant trials

The extensive Herceptin® adjuvant trial programme will

– investigate complementary strategies

– establish the efficacy and role of Herceptin® in the adjuvant setting

– establish the safety profile of Herceptin®

– determine the optimal duration of adjuvant Herceptin® therapy

Herceptin in the adjuvant setting: major trials

Four main trials are currently investigatingHerceptin® in the adjuvant setting

HERA (Herceptin® Adjuvant) Trial NSABP (National Surgical Adjuvant Breast Project)

trial B31 Intergroup trial N9831 BCIRG (Breast Cancer International Research Group)

trial 006

HERA TRIAL: study design

Herceptin®

q3w x 1 yearHerceptin®

q3w x 2 years Observation*

Stratification

Randomisation

Primary management (surgery, [neo]adjuvant chemotherapy

± adjuvant radiotherapy)

*Observation group to receive the same follow-up as the Herceptin® treatment groups

HERA TRIAL: primary objectives

Compare disease-free survival (DFS) in patients with HER2-overexpressing breast cancer who received Herceptin® versus those who did not receive Herceptin®

– in patients treated for 1 year

– and those treated for 2 years

HERA TRIAL: secondary objectives

Overall survival, relapse-free survival and distant DFS

– 1 year of Herceptin® versus observation

– 2 years of Herceptin® versus observation

Safety and tolerability – Herceptin® versus observation

Incidence of cardiac dysfunction – Herceptin® versus observation

Treatment duration (efficacy and safety) – 1 year versus 2 years of Herceptin®

HERA TRIAL: substudies

To study PK of Herceptin®:

– in the adjuvant setting

– after 1 year versus 2 years of treatment

– with 3-weekly regimen

Correlate levels ofnatriuretic peptides and other markers

with LVEF/CHFand outcomes

Pharmacokinetic (PK) substudy

Cardiac marker substudy

TransHERAsubstudy

To establisha tissue bank

to enabletranslational

research

HERA TRIAL: study size and duration

Number of centres: ~600

Sample size: 3,192 (1,064 per arm)

Target population: women with HER2-positive primary breast cancer (IHC 3+ or FISH positive)

Study duration

– recruitment 48 months

– follow-up until 10 years after last patient enrolled

HERA TRIAL: planned duration

2003 2004 2005 2006 20072002 20162008

Interimsafety

analysesEnrolmentcomplete

Main efficacy analysis

Enrolment starts

Interimefficacy analysis

10-yearfollow-up complete

Enrolment Follow-up

HERA TRIAL: key inclusion criteria

Invasive, non-metastatic, operable primary breast cancer –histologically confirmed and adequately excised

Axillary node positive, or node negative with tumour size >1cm

Known hormone receptor status (ER/PgR or ER alone)

Completed 4 cycles of approved (neo)adjuvant chemotherapy

Baseline LVEF >55% (echocardiography or MUGA scan)

Completed radiotherapy if indicated

Centrally confirmed HER2 overexpression (IHC 3+ or FISH positive) in invasive component of primary tumour

HERA TRIAL: key exclusioncriteria

Clinical T4 tumour, including inflammatory breast cancer

Cumulative dose of doxorubicin >360mg/m2 or epirubicin >720mg/m2

(Neo)adjuvant chemotherapy with peripheral blood/bone marrow stem cell support

Supraclavicular lymph node involvement

Any prior malignant neoplasms (including primary invasive breast cancer), except– curatively treated basal/squamous cell carcinoma of skin– curatively treated in-situ cervical carcinoma

HERA TRIAL: unique features

Investigating the role of Herceptin® independently from chemotherapy regimen

Investigating 2 years of Herceptin® treatment

3-weekly schedule from the start

– more convenient

– gives similar exposure to Herceptin® as weekly administration of lower doses

New model of partnership between academia and pharmaceutical industry

NSABP trial B-31: study design

*Tamoxifen for ER+ or PgR+; tamoxifen optional for ER– and PgR– patients 50 years old

Operable breast cancerHER2-positive tumour

Pathologically positive axillary nodes

Randomisation

AC x 4*

Paclitaxel x 4

AC x 4*

Paclitaxel x 4 + Herceptin®

NSABP trial B31: treatment plan

Doxorubicin 60mg/m2

Cyclophosphamide 600mg/m2

Paclitaxel 175mg/m2 q3w

Herceptin® – loading dose 4mg/kg on week 1– maintenance dose 2mg/kg x 51 weeks

AC

NSABP trial B31: primary objectives

Stage I: (n=1,000)

– evaluation of cardiac safety

Stage II: (n=1,700; total=2,700)

– evaluation of efficacy

• survival: primary endpoint

• disease-free survival (DFS): secondary endpoint

NSABP trial B31: secondary objectives

Prognostic and predictive value of phosphorylated HER2 receptor

Prognostic and predictive value of shed extracellular domain (ECD)

Concordance between different HER2 assays, i.e. IHC versus FISH

Change in HER2-phosphorylated receptor, ECD level or HER2 overexpression upon relapse

NSABP trial B31: key inclusion criteria

Histologically/cytologically proven invasive adenocarcinoma of the breast

At least one positive axillary node Axillary dissection AND either total mastectomy OR

lumpectomy HER2 overexpression (IHC 3+ or FISH positive) Known hormone receptor status (ER/PgR) No more than 84 days since prior surgery for breast cancer No prior chemotherapy, radiotherapy or hormonal therapy

for breast cancer Normal cardiac, renal and hepatic function

NSABP trial B31: patient accrual

1,200

1,000

800

600

400

200

00 4 8 12 16 20 24

Months

Nu

mb

er o

f p

atie

nts

Actual

Projected

NSABP trial B31: overall toxicity

50

40

30

20

10

0

Per

cen

tag

e o

f p

atie

nts

2 3 4 5

Grade of overall toxicity

P (n=251)P + H (n=245)

NSABP trial B31: toxicity (paclitaxel versus paclitaxel plus Herceptin®)

Neutropenicinfection

Febrileneutropenia

0 1 2

Percentage of patients

Grade 3

Grade 4

P

P + H

P

NSABP trial B31: toxicity (paclitaxel versus paclitaxel plus Herceptin®)

Sensoryneuropathy

Arthralgia

Myalgia

Fatigue

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

P

P + H

P

P + H

P

P + H

P

P + H

Grade 2

Grade 3

Percentage of patients

Intergroup trial N9831: study design

Operable breast cancerHER2-positive tumour

Node positive

Randomisation

AC q3w x 4

Paclitaxel x 12

AC q3w x 4

Paclitaxel x 12+ Herceptin

® x 12

Herceptin® x 40

AC q3w x 4

Paclitaxel x 12 + Herceptin

® x 52

Intergroup trial N9831: treatment plan Herceptin®

– 4mg/kg loading dose (90 minutes i.v. infusion) followed by 4mg/kg weekly (90 minutes i.v. infusion or 30 minutes i.v. infusion based on toxicity)

Doxorubicin 60mg/m2 every 3 weeks

Cyclophosphamide 600mg/m2 every 3 weeks

Paclitaxel 80mg/m2 weekly

Intergroup trial N9831: objectives

Primary– disease-free survival – cardiotoxicity

Secondary– overall survival – evaluation of whether sHER1 or sHER2 levels

at baseline are prognostic for disease-free and overall survival

– concordance of IHC (HercepTest®) with FISH (VysisTM); disease-free survival; and overall survival

Intergroup trial N9831: inclusion criteria Operable, histologically confirmed adenocarcinoma of

the breast Node-positive disease Hormonal status known (ER/PgR) HER2 overexpression (IHC 3+ or FISH positive) No prior chemotherapy

– hormonal therapy allowed for up to 4 weeks but discontinued prior to enrolment

No more than 84 days from mastectomy or axillary node dissection

LVEF normal

Intergroup trial N9831: exclusion criteria Locally advanced tumours Prior history of breast cancer Prior chemotherapy or radiotherapy for breast cancer Cardiac disease including:

– myocardial infarction– history of congestive heart failure– medication for arrythmia or angina pectoris

Prior anthracycline or taxane therapy for any malignancy

Intergroup trial N9831: cardiotoxicity

Arm 3 suspended due to a few cardiotoxic events

This arm was reopened following the first interim safety analysis in June 2002 and patient accrual continues

At first interim analysis cardiotoxicity remained within acceptable limits based on review Data Monitoring Committee

Intergroup trialN9831

NSABP trial B31

Arm 3: AC x 4 paclitaxel 80mg/m2

qw x 12 with weekly Herceptin® Arm 2: AC x 4 paclitaxel 175mg/m2

q3w x 4 with weekly Herceptin®

BCIRG trial 006: study design

AC x 4 Docetaxel + cisplatin or carboplatin x 6

+ Herceptin® weekly 3-weekly Herceptin® for 1 year from date

of first administration

Docetaxel x 4

Operable node-positive, HER2-positive (FISH) breast cancer

AC x 4

Docetaxel x 4 + Herceptin® weekly 3-weekly Herceptin® for 1 year from date

of first administration

Randomisation

BCIRG trial 006: treatment plan

Doxorubicin 60mg/m2

Cyclophosphamide 600mg/m2

Docetaxel 100mg/m2

Platinum salt

– carboplatin AUC 6

– cisplatin 75mg/m2

Herceptin®

– 6mg/kg every 3 weeks

BCIRG trial 006: objectives

Primary – disease-free survival

Secondary– overall survival– safety– cardiac toxicity– quality of life – prognostic value of HER2 overexpression

BCIRG trial 006: key inclusion criteria

Histologically proven breast cancer Definitive surgical treatment Node-positive/negative disease HER2 overexpression (FISH positive) Normal renal, hepatic and cardiac function No prior systemic therapy or radiotherapy for breast

cancer

Comparison of the four large Herceptin® adjuvant trials

Trial

Target accrual

Patient

selection

Accrual phase (years)

Follow-up phase (years)

Primary endpoint

NSABP B31 2,700 Node+, IHC 3+ or

FISH+

4.75 15 OS

Intergroup N9831

3,000 Node+, IHC 3+ or

FISH+

4.5 15 DFS

BCIRG 006 3,000 Node+ and – FISH+

NA NA DFS

HERA Trial 3,192 Node+ and – IHC 3+ or

FISH+

4 10 DFS

OS = overall survivalDFS = disease-free survival

Other Herceptin® adjuvant trials:ECOG trial E2198

234 anthracycline-naive patientsIHC 2+/3+

Paclitaxel + Herceptin®

AC observation

Paclitaxel + Herceptin®

Sledge G, et al. Breast Cancer Res Treat 2001;69:209 (Abstract 4)

AC Herceptin®

ECOG trial E2198: inclusion criteria

Histologically confirmed stage II or IIIa adenocarcinoma of the breast

HER2 overexpression (IHC 2+/3+) Axillary node dissection AND mastectomy or

lumpectomy within 12 weeks prior to enrolment No prior chemotherapy, hormonal therapy (at least

one year since tamoxifen therapy) or radiotherapy No history of cardiac disease

ECOG trial E2198: objectives

Evaluate the incidence of cardiotoxicity associated with paclitaxel plus Herceptin® in women with HER2-positive breast cancer

Assess the long-term safety of Herceptin® in this patient population

ECOG trial E2198: cardiotoxicity

Sledge G, et al. Breast Cancer Res Treat 2001;69:209 (Abstract 4)

LVEF >10%

LVEF < normal

LVEF grade 3/4

Post paclitaxel + Herceptin®

9.5 (18/189) 2.1 (4/189) –

Post AC 12.5 (16/128) 5.5 (7/128) 8

Other Herceptin® adjuvant trials:PACS 04

Second randomisation

n=2,600(HER2 positive/negative)

First randomisation

FEC100 x 6Epirubicin + docetaxel x 6

1-year Herceptin® monotherapy

Observation

n=520(HER2 positive)

Herceptin® in the adjuvant setting: conclusions

The extensive Herceptin® adjuvant trial programme will enable the role of Herceptin® in the adjuvant setting to be defined

Using Herceptin® in the adjuvant setting may lower the risk of treatment failure and improve survival in women with HER2-positive disease