1. Herceptin ® adjuvant therapy: “a triumphal narrative of translational research” Brian Leyland-Jones McGill University Department of Oncology Montreal, Quebec, Canada Burstein, H. NEJM 2005:353;1652

2. NSABP B-31 (US) (n=1960) Paclitaxel q3w x 4 or qw x 12 Paclitaxel q3w x 4 or qw x 12 + H qw HERA Trial (ex- US) (n=5090) Observation H q3w* x 12 months H q3w* x 24 months Any CT ± RT Intergroup N9831 (US) (n=3046) Paclitaxel qw x 12 Paclitaxel qw x 12 + H qw BCIRG 006 (global) (n=3222) Carboplatin + docetaxel q3w x 6 + H qw Herceptin ® adjuvant trials (>13,000 patients) H qw AC x 4 Docetaxel q3w x 4 Docetaxel q3w x 4 + H qw *q3w at 6mg/kg H = Herceptin ® H q3w* AC x 4

3. Herceptin ® in the adjuvant setting: how four trials complement each other Covers all currently accepted EU and US treatment strategies Combinations of a number of regimens and both taxanes Compares AC followed by H with novel treatment concepts Investigates optimal treatment duration Investigates sequential versus combination therapy

4. Joint analysis: disease-free survival Years from randomisation Romond et al 2005 87% 85% 67% 75% HR=0.48; p<0.0001 100 90 80 70 60 50 012345 2-year median follow-up Patients (%) AC T AC TH nEvents ACTH1672133 ACTP1679261

5. Joint analysis: time to first distant recurrence N Events 012345 50 60 70 80 90 100 AC  TH 1672 96 AC  T 1679 194 HR=0.47, 2P=8x10 -10 AC  TH AC  T Years from randomization 90% 90% 81% 74% % Romond et al 2005

6. Joint analysis: hazard of distant recurrence 0 1234 0 20 40 60 80 100 120 Rate per 1000 Women /Yr Years from randomization AC  TH AC  T Romond et al 2005

7. Joint analysis: overall survival Romond et al 2005 AC  TH 94% 91% 87% 92% AC  T NDeaths AC  T167992 AC  TH167262 HR=0.67, 2P=0.015 % 100 90 80 70 60 50 012345012345 Years from randomisation

8. 0.50.32.61472 1.00.53.61202 1.50.53.9983 2.00.54.1775 2.50.84.1595 3.00.84.1405 NSABP B-31: cumulative incidence of cardiac events in the evaluable cohort Yrs Post Day 1 Cyc 5 Cum Inc Arm 1 (%) Cum Inc Arm2 (%) Number At Risk Arm 2: AC→PTX + H N=850, 31 CHFs, No Cardiac Deaths Arm 1: AC→PTX N=814, 4 CHFs, 1 Cardiac Death HR=5.9 4.1% 0.8%

9. NSABP-B31: post – AC LVEF and age are independent predictors of Herceptin ® - associated CHF Age and LVEF were statistically significant predictors of CHF. Careful cardiac monitoring must be done. LVEFAge < 50Age ≥ 50 50 – 543/48 (6.3%)9/47 (19.1%) 55 – 645/229 (2.2%)10/194 (5.2%) 65+1/160 (0.6%)2/159 (1.3%) P(Age) = 0.04 P(LVEF) < 0.001

10. Joint analysis: conclusions Herceptin ® given concurrently with paclitaxel following AC –significantly reduces the risk of DFS events by 52% –significantly reduces the risk of distant recurrence by 53% –significantly improves overall survival, with a 33% reduced risk of mortality The number of cardiac events was low –<4% incidence, Herceptin ® versus non-Herceptin ® in both trials

11. HERA: key inclusion criteria Centrally confirmed HER-2 overexpression or amplification Centrally confirmed HER-2 overexpression or amplification Node-positive or (sentinel) node-negative with  T1c Node-positive or (sentinel) node-negative with  T1c Completed  4 cycles of approved (neo)adjuvant chemotherapy regimen Completed  4 cycles of approved (neo)adjuvant chemotherapy regimen Baseline LVEF  55% (Echo or MUGA) Baseline LVEF  55% (Echo or MUGA) Known hormone receptor status Known hormone receptor status Piccart-Gebhart et al 2005

12. HERA: patient and tumour characteristics (%) Observation (n=1,693) 1-year Herceptin (n=1,694) Age (years) <35 35–49 50–59 ≥60 7.3 43.7 32.7 16.2 7.6 44.3 31.8 16.2 Adjuvant CT (%) No AC, no T AC AC + T 6.1 68.3 25.5 6.2 67.9 26.0 Nodal status Any (neoadjuvant) Node-negative 1–3 + ≥4 + 10.2 32.9 28.9 27.9 11.1 32.1 28.5 28.3 Hormone Receptor (%) HR-negative HR-positive 49.9 50.0 49.0 50.9 AC=anthracycline; T=taxane Piccart-Gebhart et al 2005

13. HERA: endpoints and analysis plan Target accrual was 4,482 patients, 5,090 enrolled –HR=0.77 (80% power two sided α=0.025) for nil versus 1 year, nil versus 2 years Primary endpoint DFS Secondary endpoints RFS, DDFS, OS, 2 years versus 1-year Herceptin ® One interim efficacy analysis (n=475 events), 1 year median follow up One primary core analysis (n=951 events) Safety – tolerability, incidence of cardiac dysfunction Three safety interim analyses of cardiac endpoints after n=300, 600, 900 patients. Stopping rule ≥4% increase in cardiac events Piccart-Gebhart et al 2005

14. 100 80 60 40 20 0 Patients (%) Months from randomisation 6 121218182424 16931108767445224 16941172885532 268 127 220 1 year Herceptin ® Observation 0 No. at risk EventsHR95% CIp value 0.54 0.43, 0.67<0.0001 2-year DFS 85.8 77.4 HERA: disease-free survival Median follow-up: 1 year; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval Piccart-Gebhart et al 2005

15. HERA: efficacy endpoints HR 95% CI p value 2-year outcome, % 0.49 0.38, 0.63 <0.0001 82.8 vs 90.6 0.76 0.47, 1.23 0.26 95.1 vs 96.0 Distant recurrence Overall mortality No. events 1718937 29 Observation 1 year Herceptin ® Piccart-Gebhart et al 2005 0.54 0.43, 0.67 <0.0001 77.4 vs 85.8 DFS 220 127

16. HERA: cardiac safety Cardiac events have been manageable and reversible Decrease by >10 EF points and LVEF <50% a Symptomatic CHF, including severe CHF Severe CHF Cardiac death Observation 2.2 0.06 0 0.06 1 year Herceptin 7.1 1.7 0.5 0 % patients a Many were single observations not confirmed at subsequent time points p value <0.001 0.002 1.0 Piccart-Gebhart et al 2005CHF = congestive heart failure

17. HERA: conclusions At 1-year follow up, Herceptin ® given after chemotherapy –significantly reduces the risk of DFS events by 46% –significantly reduces the risk of distant recurrence by 51% –is associated with a low incidence of severe CHF (0.5%) Piccart-Gebhart et al 2005

18. BCIRG 006: disease-free survival % Disease Free 0.6 0.7 0.8 0.9 1.0 012345 Year from randomization 77% 86% 80% 73% 84% 80%86% 93% 91% Patients Events 1073147AC->T 107477AC->TH 107598TCH HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001 HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002 Slamon et al SABCS 2005

19. BCIRG 006: mean LVEF - all observations AC->T (N=1012) AC->TH (N=1040) TCH (N=1029) AC->T TCH AC->TH 189 pts 290 pts 205 pts Slamon et al SABCS 2005

20. BCIRG 006: HER2 and TOPO II HER2 core region 17q 1217q 21.117q 21.2 60% n=2120 4% Topo II Non co-amplified Slamon et al 2005 Normal AmplifiedDeletion TOPO II region 35% Co-amplified 2120 of 3222 patients analysed

21. BCIRG 006: disease-free survival non-amplified Topo II by arm % Disease Free Months 0.0 0.6 0.8 1.0 061218243036424854 Patients EventsTreatment 45892AC->T 47245AC->TH 44654TCH Logrank P= <0.001 TCH AC->TH AC->T Press et al SABCS 2005

22. BCIRG 006: disease-free survival amplified Topo II by arm % Disease Free Months 0.5 0.6 0.8 1.0 061218243036424854 Patients EventsTreatment 22723 AC->T 26513AC->TH 25221TCH Logrank P= 0.24 TCH AC->TH AC->T Press et al SABCS 2005

23. BCIRG 006: conclusions Herceptin ® provided a significant DFS benefit in both regimens –in combination with docetaxel after AC (HR=0.49) –in combination with docetaxel and carboplatin without an anthracycline (HR=0.61) It is too early to tell whether a non-anthracycline- containing Herceptin ® regimen has efficacy comparable to anthracycline-based regimens Cardiac safety appears to be higher with non- anthracycline-based therapy Slamon et al 2005

24. FinHER: trial design 502 pts. Docetaxel 507 pts. Vinorelbine 1010 pts. EBC pN+ or pN0 (tumour >2 cm, PR-) R 115 pts. HER2 + 392 pts. HER2 - 116 pts. HER2 + 386 pts. HER2 - R R 57 pts. + Herceptin ® 58 pts. 58 pts. + Herceptin ® 58 pts. 392 pts. HER2 - 386 pts. HER2 - 1010 patients were recruited and after 2 randomisations allocated to 6 treatment arms (1 patient excluded from efficacy analyses)

25. FinHER: recurrence-free survival in HER2-positive subgroup 100 80 60 40 20 0 Recurrence-free survival (%) 0123401234 Time (years) 89.3% 77.6% Herceptin Events=12 No Herceptin Events=27

26. FinHER: cardiac safety in HER2-positive subgroup Cardiac failure LVEF decrease >15% from baseline Joensuu et al 2005 Herceptin ® 0 (0%) 4 (3%) No Herceptin ® 1 (1%) 7 (6%)

27. FinHER: conclusions Compared with vinorelbine, adjuvant docetaxel –improves DFS –results in more adverse events Brief use of adjuvant Herceptin ® administered concomitantly with docetaxel or vinorelbine was well-tolerated and effective for HER2-positive breast cancer and warrants further study

28. Summary: Herceptin ® in EBC 012 HERA1 year Combined analysis2 years Median follow-up Favours Herceptin ® Favours no Herceptin ® HR BCIRG 006 DCarboH2 years BCIRG 006 AC DH FinHER VH / DH CEF3 years Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2005; Joensuu et al 2005

29. Summary: Herceptin ® in EBC Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2005; Tan-Chiu et al 2005 Trial HERA NSABP B-31 NCCTG N9831 BCIRG 006 FinHER Arm H 1 year Nil AC  P AC  PH AC  D AC  DH DCarboH H No H Baseline LVEF, % >55 >50 CHF, n (%) 0 9 (0.5) 4 (0.8) a 31 (4.1) a 0 a 20 (2.9) a 3 (0.3) 17 (1.6) 4 (0.4) 0 (0) 1 (1) a Cumulative percent Cardiac death, n 1 0 0 0 00

30. Herceptin ® adjuvant therapy: conclusions and future prospects Benefits seen with Herceptin ® are independent of chemotherapy and patient characteristics Radiotherapy can be given before or concurrent with Herceptin ® Data are currently not available on benefit of Herceptin ® –as monotherapy or combined with endocrine agents in patients not indicated for chemotherapy –in patients with primary tumours <1cm Five studies have demonstrated a substantial DFS advantage with adjuvant Herceptin ® in women with HER2-positive EBC Optimal duration of treatment is uncertain

31. Herceptin ® in the news Herceptin is the cure for early stages of breast cancer? MedIndia, India, Jan 06 …thanks to Herceptin, breast cancer sufferers could now look forward to a long life The Observer, UK, Jan 06 … superdrug that has changed the face of modern medicine The Observer, UK, Jan 06 Cancer wonder drug campaigner gets all clear Mirror.co.uk, Jan 06 “Herceptin is the best chance for women like me” Barbara Clarke, Telegraph.co.uk, Jan 06