Moving forward: Herceptin® in the adjuvant setting – Trials in which

Herceptin® is combined with chemotherapy

Elizabeth Tan-ChiuMedical Oversight NSABP Operations Office

Pittsburgh, Pennsylvania, USA

NSABP B-31

*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 B-31 stratification

Operable breast cancerHER2-positive tumour

Pathologically positive axillary nodes

Stratification Number of positive nodes Type of surgery Tamoxifen administration Type of radiation therapy

Primary aim

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

Eligibility

Node positive

HER2 positive: IHC 3+ or FISH+

Normal MUGA

No previous history of significant

cardiac disease

Drug dose

Adriamycin 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

MUGA schedule

Arm IAC Paclitaxel

18months

6months

9months

3months

0months

0months

18months

6months

9months

3months

Arm IIAC Paclitaxel + Herceptin®

Post-AC left ventricular ejection fraction (LVEF) in asymptomatic patients

Absolute decrease in LVEF betweenbaseline and 3 weeks after last AC cycle Herceptin®

<10% Initiate

10–15%, at or above LLN* Initiate

10–15% and below LLN Prohibit

≥16% regardless LLN Prohibit

*LLN = lower limit of normal

Herceptin® management in asymptomatic patients

*Repeat MUGA after 4 weeks

Relationship ofLVEF to LLN

Decreaseof <10%

Decreaseof 10–15%

Decreaseof ≥16%

Within normal limits Continued Continued Hold*

1–5% below LLN Continued Hold* Hold*

≥6% below LLN Continued Hold* Hold*

Secondary aim

Tissue-block collection

– primary tumour

– involved lymph node

– relapse tissue, if biopsied

Serum collection

– at entry

– at relapse

Secondary aim (cont’d)

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 receptor phosphorylation, ECD level or HER2 overexpression upon relapse

B-31 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

Projected

Actual

Patient characteristics

Age (years) Race No. of positive nodes

≤3940

–49

50–5

9

≥60

White

Black

Oth

er 1–3

4–9

10+

AC → P

AC → P + H

100

80

60

40

20

0

Per

cen

tag

e o

f p

atie

nts

AC = anthracycline/cyclophosphamide; P = paclitaxel; H = Herceptin®

Pathological tumour size (cm)

≤1.0

1.1–

2.0

2.1–

3.0

3.1–

4.0

4.1–

5.0

≥5.1

AC → P (mean 2.9cm)

AC → P + H (mean 2.8cm)

100

80

60

40

20

0

Per

cen

tag

e o

f p

atie

nts

Patient characteristics

Operation and radiotherapy Tamoxifen treatment

AC → P

AC → P + H

Mas

tect

omy

+

no ra

diot

hera

pyM

aste

ctom

y +

left

and/

or rig

ht

radi

othe

rapy

Lum

pect

omy

+

left

radi

othe

rapy

Lum

pect

omy

+

left

and

right

radio

ther

apy

No tam

oxife

n

Recei

ved

tam

oxife

n

100

80

60

40

20

0

Per

cen

tag

e o

f p

atie

nts

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

AC (n=615)

Overall toxicity (cont’d)

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)

Toxicity in patients receiving paclitaxel (n=251) versus paclitaxel plus Herceptin® (n=245)

Neutropenicinfection

Febrileneutropenia

0 1 2

Percentage of patients

Grade 3

Grade 4

P

P + H

P

Toxicity in patients receiving paclitaxel (n=251) versus paclitaxel plus Herceptin® (n=245)

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

Cardiac toxicity assessments

Three formal interim statistical comparisons per arm:

1) after 100 evaluable patients

2) after 300 evaluable patients

3) after 500 evaluable patients

treated and followed for at least 6 months after start of Herceptin®

NSABP B-31: cardiac monitoring

At its first interim analysis, the cardiotoxicity (LV dysfunction) remains within acceptable limits as reviewed by the Data Monitoring Committee (DMC)

Initial submittedresult

CentralHercepTest®

<3+

Central FISH(PathVysionTM)

negative

Both centralassays

negative

HercepTest® 3+ 1/28 1/28 1/28 (4%)

Other IHCpositives 0/1 0/1 0/1 (0%)

Total 1/29 1/29 1/29 (3%)

HER2 retesting at control reference laboratory (Lab Corp): initial test done at large volume* laboratories

*More than 100 assays/month

HER2 retesting at control reference laboratory (Lab Corp): initial test done at smaller volume* laboratories

Initial submittedresult

CentralHercepTest®

<3+

Central FISH(PathVysionTM)

negative

Both centralassays

negative

HercepTest® 3+ 10/52 12/58 10/52 (19%)

Other IHCpositives 11/23 9/23 8/23 (35%)

Total 21/75 21/75 18/75 (24%)

*Less than 100 assays/month

Lab corp

Amplified Not amplified

Amplified 62 1NSABPpathologylaboratory

Not amplified 3 15

Central FISH (PathVysionTM): correlation between reference laboratory (Lab Corp) and NSABP pathology laboratory retesting

77/81 = 95% correlation

NSABP B-31 amendment

HER2 assays by IHC must be done at an NSABP-approved reference laboratory

HER2 by FISH may be done at any laboratory

Herceptin® adjuvant therapy: summary of ongoing trials

*H q3w at 6mg/kg

NSABP B-31Paclitaxel q3w x 4

Paclitaxel q3w x 4 + HAC x 4

HERA TrialH q3w* x 12 monthsH q3w* x 24 monthsObservation

Any CT and/or RT

Intergroup N9831

Paclitaxel qw x 12

Paclitaxel qw x 12

Paclitaxel qw x 12 + H

AC x 4

BCIRG 006 Docetaxel q3w x 4AC x 4

AC x 4 Docetaxel q3w x 4 + H

Carboplatin + docetaxel q3w x 6 + H

H