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

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

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

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

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

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

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

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

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 0.63 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

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

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.