1. Herceptin® (trastuzumab) in combination with chemotherapy: pivotal metastatic breast cancer survival data 1

2. Summary of HO648g trial design
AC q3w x 6 cycles
(n=138)
No prior anthracyclines
n=281
AC q3w x 6 cycles + Herceptin (trastuzumab) 4 mg/kg loading, then 2 mg/kg qw until PD (n=143)
HER2-positive MBC (IHC 3+ or 2+)
No prior chemotherapy for MBC (n=469)
Paclitaxel 175 mg/m2
q3w x 6 cycles (n=96)
Prior adjuvant anthracyclines
n=188
Reference
Slamon DJ et al. N Engl J Med 2001; 344: 783–792.
Paclitaxel 175 mg/m2 q3w x 6 cycles + Herceptin (trastuzumab) 4 mg/kg loading, then 2 mg/kg qw until PD (n=92)
AC, doxorubicin 60 mg/m2 or epirubicin 75 mg/m2 & cyclophosphamide 600 mg/m2 HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; IHC, immunohistochemistry; PD, progressive disease; q3w, every 3 weeks; qw, every week
Slamon et al 2001 2

3. H0648g: overall survival (IHC 3+ and taxane subgroup)
Probability of survival
1.0
Herceptin (trastuzumab) + paclitaxel (n=68)
Paclitaxel (n=77)
0.8
0.6
0.4
0.2
+40%
Reference
Smith IE et al. Anticancer Drugs 2001; 12 (Suppl 4): S3–S10.
17.9
24.8
0.0 5 10 15 20 25 30 35 40 45
Months
6.9 months
IHC 2+ tumours were not confirmed for HER2-positivity by in situ hybridisation Subgroup analysis, p value not reported;
OS, overall survival
Smith 2001 3

4. Summary of M77001 trial design
HER2-positive MBC (IHC 3+ and / or FISH+)
No prior chemotherapy for MBC
Baseline LVEF >50% (n=186)
Docetaxel 100 mg/m2
q3w x 6 cycles
(n=94a)
Docetaxel 100 mg/m2 q3w x 6 cycles + Herceptin (trastuzumab) 4 mg/kg loading, then 2 mg/kg qw until PD (n=92b)
Reference
Marty M et al. J Clin Oncol 2005; 23: 4265–4274.
aAdditional cycles of docetaxel administered at investigator’s discretion. Patients progressing on docetaxel alone could cross over to receive Herceptin (trastuzumab); b2 patients did not receive study medication FISH, fluorescence in situ hybridisation;
LVEF, left ventricular ejection fraction
Marty et al 2005 4

5. M77001: overall survival (IHC 3+ / FISH+)
Patients alive (%)
100
Herceptin (trastuzumab) + docetaxel (n=92)
Docetaxel alone (n=94) 80
p=0.0325* 60 40 20
+37%
22.7
31.2
References
Extra J–M et al. J Clin Oncol (Meeting Abstracts) 2005; 23: 16S–17S.
Marty M et al. J Clin Oncol 2005; 23: 4265–4274. 5 10 15 20 25 30 35 40 45 50
Months
8.5 months
*Statistically significant difference
Marty et al 2005 5

6. Herceptin (trastuzumab) MBC pivotal trials: TTP
TTP, months
7.1 vs. 3.0
11.7 vs. 6.1
Increase, %
137 92
Treatment
Paclitaxel ± Ha
Docetaxel ± H n
145
186
References
Slamon DJ et al. N Engl J Med 2001; 344: 783–792.
Smith IE. Anticancer Drugs 2001; 12 (Suppl 4): S3–S10.
Marty M et al. J Clin Oncol 2005; 23: 4265–4274.
aPatients with HER2 IHC 3+ MBC: all patients had received adjuvant anthracyclines TTP, time to progression; H, Herceptin (trastuzumab)
Slamon et al 2001; Smith et al 2001; Marty et al 2005 6

7. Safety profile: Herceptin (trastuzumab) plus chemotherapy vs
Safety profile: Herceptin (trastuzumab) plus chemotherapy vs. chemotherapy
Paclitaxela
Docetaxel
SAE, %
Fever
Heart failure
Leucopeniab
Febrile neutropenia
Alopecia
Alone (n=95) 1 5 – 26
H (n=91) 2 6 – 26
Diff 1 –
Alone (n=94) 1 15 17 6
H (n=92) 1 20 23 10
Diff 1 5 6 4
References
Slamon DJ et al. N Engl J Med 2001; 344: 783–792.
Marty M et al. J Clin Oncol 2005; 23: 4265–4274.
aAll patients who received paclitaxel ± H; bBased on pretreatment blood counts only SAE, serious adverse event; Diff, difference
Slamon et al 2001; Marty et al 2005 7

8. Summary of TAnDEM trial design
Anastrozole 1 mg daily + Herceptin (trastuzumab)
4 mg/kg loading dose  2 mg/kg qw until PD (n=103)
HER2-positive, hormone receptor-positive MBC (n=208a) R
Anastrozole 1 mg daily until PD (n=104)
Reference
Kaufman B et al. J Clin Oncol 2009; 27: 5529–5537.
Crossover to receive Herceptin (trastuzumab) was actively offered to all patients who progressed on anastrozole alone (n=73/104)
a1 patient did not receive study drug and was excluded from analyses
Kaufman et al 2009 8

9. TAnDEM: PFS Probability 1.0 0.8 Events 87 99 Median PFS 4.8 months
95% CI
3.7, 7.0
2.0, 4.6
p value
0.0016
0.6
HR CI (0.47, 0.84)
0.4
0.2
0.0 5 10 15 20 25 30 35 40 45 50 55 60
Reference
Kaufman B et al. J Clin Oncol 2009; 27: 5529–5537.
Months
2.4 months
No. at risk
A+H
103 48 31 17 14 13 11 9 4 1 1 A
104 36 22 9 5 4 2 1
PFS, progression-free survival (time from randomisation to date of PD or death); CI, confidence interval; A, anastrozole
Kaufman et al 2009 9

10. Safety profile: Herceptin (trastuzumab) plus anastrozole vs
Safety profile: Herceptin (trastuzumab) plus anastrozole vs. anastrozole
Patients, %
Cardiac disorders
Asymptomatic CHF (NYHA class I)
Symptomatic CHF (NYHA class II)
Myocardial infarction, ischaemia
Confirmed decrease in LVEFC >1 AE
>1 SAE
Death due to AE
Grade 3/4 AEs
A + H (n=103)
A (n=104) 13 4a 1 2
1 87 23 28 2 1
0 65 6 2b 16
Reference
Kaufman B et al. J Clin Oncol 2009; 27: 5529–5537.
a1 patient had a myocardial infarction and subsequent CHF class I; b1 event occurred after crossover to A + H; C1 patient had asymptomatic decreases ≥15 LVEF percentage points from baseline to <50%
CHF, congestive heart failure; NYHA, New York Heart Association
Kaufman et al 2009 10

11. References
Kaufman B, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 2009; 27:5529–5537.
Marty M, et al. Randomized Phase II Trial of the Efficacy and Safety of Trastuzumab Combined With Docetaxel in Patients With Human Epidermal Growth Factor Receptor2–Positive Metastatic Breast Cancer Administered As First-Line Treatment: The M77001 Study Group. J Clin Oncol 2005; 23:4265–4274.
Slamon DJ, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783–92.
Smith IE. Efficacy and safety of Herceptin® in women with metastatic breast cancer: results from pivotal clinical studies. Anti-Cancer Drugs 2001; 12:S3–S10.