1. Targeted therapy in Early Breast Cancer Paul Ellis Guy’s Hospital, London

3. Targeted therapy Key principles for targeted therapeutics: –the target must be relevant to the disease –a clear scientific rationale must exist for the therapeutic –patients can be selected for on basis of tumour expression of the target Questions for clinical trials of targeted therapeutics: –Are the most appropriate population of patients being treated? –Has the trial been designed correctly, with most appropriate biological / clinical endpoints?

4. Molecular targets: –Hormone Receptors ER, PgR AR –Cell Surface Receptors HER family (EGFR, HER2) IGFR-I –Angiogenesis –PARP –Signal Transduction Src MEK PI3-Kinase / Akt mTOR HSP-90 Treatment choices based on molecular features: ER / PgR positive HER2 positive Basal type (triple negative) ? BRCA status ? Targeted Therapy of Breast Cancer 2008

5. Background HER2 positive EBC Global Adjuvant trial update Current UK practice Application of targeted therapies Neoadjuvant therapy Triple Negative EBC Summary

6. HER2+ EBC

7. Drugs to block HER Family Receptors Tyrosine kinase inhibitors EGFR: gefitinib, erlotinib HER2: AEE-788, lapatinib Pan-erb: CI-1033, HKI-569 Monoclonal antibodies cetuximab, ABX-EGF, EMD72000, h-R3, trastuzumab, pertuzumab Signal Transduction RR Ligand K K

8. Adjuvant trastuzumab trials: >13,000 patients NCCTG N9831 (USA) HERA (ex-USA) BCIRG 006 (global) NSABP B-31 (USA) Piccart-Gebhart et al 2005; Romond et al 2005; Slamon et al 2006 IHC or FISH (n=5090) DocetaxelDocetaxel + carboplatinDoxorubicin + cyclophosphamidePaclitaxel

9. ASCO 2007: Updated N9831/B-31 Joint Analysis: DFS 16846087531,2351,800 Number at risk N=619 events HR* adj = 0.48 (95% CI: 0.41-0.57) *Nodes, receptor status, paclitaxel schedule, protocol 73.1 % 86.4% 0 20 40 60 80 100 01234567 Follow-up (yrs) Alive and disease-free (%) AC  P (n=1,979; 397 events) P < 0.00001 77.6 % 20252248681,3471,854 85.9% 92.3% AC  P+ H (n=1,989; 222 events) 87.9 % *Intent to treat events: recurrent disease, contralateral bc, 2nd primary, death 21% crossover

10. a Based on small subgroups of patients with HER2-positive breast cancer; b relapse-free survival; V, vinorelbine CEF, cyclophosphamide, epirubicin, 5-fluorouracil DFS benefit across 5 out of 6 trials 4 2 3 4 Joensuu et al 2006; Slamon et al 2006 Perez et al 2007; Smith et al 2007 Spielmann et al 2007 3 3 Median follow-up, years 012 Favours Herceptin Favours no Herceptin HR DFS benefit B-31 / N9831 AC  PH HERA CTx  H 1 year FinHer a VH / DH  CEF b PACS-04 a CTx  H 1 year BCIRG 006 AC  DH BCIRG 006 DCarboH

11. 01 2 Favours Herceptin Favours no Herceptin HR Adjuvant trastuzumab trials: proven OS benefit B-31 / N9831 AC  PH BCIRG 006 AC  DH HERA H 1 year BCIRG 006 DCarboH FinHer VH / DH a 4 3 2 Median follow-up, years 3 Joensuu et al 2006; Perez et al 2007; Slamon et al 2006; Smith et al 2006 3

12. Cumulative incidence of cardiac events: N9831/NSABP B31 updated analysis Longer follow-up showed no additional concerns regarding the cardiac safety profile  Cardiac events occurred early  No evidence of increased toxicity or late toxicity In NSABP B 31 the following factors were shown to be predictive for CHF:  Age (p=0.03)  Hypertensive medications (p=0.02)  Baseline LVEF (p=0.0003) The incidence of cardiac events reach a plateau at around 1 year Cardiac effects of trastuzumab were largely reversible Perez et al Abs 512 ASCO 2007

13. Slamon et al 2006 Rastogi et al 2007 Suter et al 2007 Perez et al 2008 Incidence of trastuzumab-related cardiac events in EBC trials 3.0 NR 18.0 8.6 Asymptomatic LVEF decline, %a H 1 year AC  PH AC  DH DCarboH Arm HERA NSABP B-31 NCCTG N9831 BCIRG 006 1,678 947 570 1,068 1,056 n Severe CHF, % 0.6 3.8cum (5 yr) 3.3cum (3 yr) 1.9 0.4 Cardiac death, n 0000000000

14. Ongoing Trial Questions Duration -Greater than 1 yr (HERA 1 v 2 yr awaited - ? SA 08 ) -Shorter – 6 v 12 months (Separate UK & French trials) Concurrent or Sequential -N 9831 update - ? SA 09 Older / Lower risk patients -Herceptin needed in addition to AI? Can we do without anthracyclines? Translational Biology –How do we Identify subgroups that gain most benefit?

15. a Based on small subgroups of patients with HER2-positive breast cancer; b relapse-free survival; V, vinorelbine CEF, cyclophosphamide, epirubicin, 5-fluorouracil Duration: Vast majority of evidence in trials of 12 months 4 2 3 4 Joensuu et al 2006; Slamon et al 2006 Perez et al 2007; Smith et al 2007 Spielmann et al 2007 3 3 Median follow-up, years 012 Favours Herceptin Favours no Herceptin HR DFS benefit B-31 / N9831 AC  PH HERA CTx  H 1 year FinHer a VH / DH  CEF b PACS-04 a CTx  H 1 year BCIRG 006 AC  DH BCIRG 006 DCarboH

16. What is the optimum scheduling of Herceptin and chemotherapy? HERA 0.18 0.16 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.00 1-67-1213-1819-2425-3031-36 Months since randomisation HR Observation 1 year H PACS-04 0.012 6 Months HR 012182430364248 0.010 0.008 0.006 0.004 0.002 1 year H Observation HR=0.57 95% CI (0.30-1.09) HR=1.04 NSABP B-31 / NCCTG N9831 120 0 Years since randomisation Rate per 1,000 women/ year 1234 100 80 60 40 20 0 AC→TH AC→T Romond et al 2005 Smith 2006 Spielmann et al 2007

17. Should we treat the “low risk” HER2+patient?

18. Poor 10-year Breast Cancer Specific Survival (BCSS) and RFS for HER2+ pT1N0 tumours 3836 tissue microarray cohort of ebc diagnosed in British Columbia 1986-92, confirmed invasive with ER and HER2 1245 cases T1pN0 (952 of these no adjuvant therapy) HER2 +ve defined as IHC 3+ or FISH+ 13% of total were HER2 +ve 9.4% of TIpN0 were HER2 +ve Norris et al. SABCS 2006. Poster 2031

19. 10-year BCSS and RFS by HER2 and ER in the pT1N0 cohort HER2- (All)HER2+ (All)HER2+ER+HER2+ER- All cases n = 3836 3336 (87%)500 (13%)204 (5.3%)296 (7.7%) 10-year BCSS 76.558.162%55.4% 10-year RFS68.549.552.2%47.6% T1pN0 n = 1245 1128 (90.6%)117 (9.4%)40 (3.2%)77 (6.2) 10-year BCSS 90.181.391.776.2 10-year RFS78.771.677.568.3 Adapted from Norris et al. SABCS 2006. Poster 2031 BCSS, breast cancer-specific survival RFS, relapse-free survival

20. Adjuvant Trastuzumab in ‘Low-Risk’ Patients:T1N0M0 T1 (≤ 1 cm ) N0 excluded from adjuvant trials T1 (> 1 cm) were recruited into HERA, N9831, and BCIRG 006 - 32% (HERA) - 29% (BCIRG006) - 11% (N9831), patients had node-negative disease In HERA 994 of 1099 N0 pts had tumours >1cm Smith IE et al. Lancet 2007; 369: 29–36 Perez EA et al. ASCO 2007. Abstract #512 Slamon D. SABCS 2006

21. DFS benefit across different tumour sizes Slamon et al 2006 Perez et al 2007; Smith et al 2007 >2-5 cm BCIRG 006 >2-5 cm >5 cm 0.00.52.51.01.52.0 0-2 cm N9831 / B-310-2 cm >5 cm AC  DH <2 cm DCarboH<2 cm ≥2 cm Favours HerceptinFavours no Herceptin HR HERA DFS, disease-free survival

22. Trastuzumab for Low Risk Breast Cancer The Contradiction St Gallen and NCCN guidelines Adjuvant CT plus trastuzumab is indicated for patients with N0 tumours if ≥ 2 cm. HERA Conclusions ‘We were unable to identify a subgroup for which the potential absolute benefit of trastuzumab was small enough to indicate that treatment might not be clinically beneficial’ (Based on 510 pts randomised with T1(1.1-2cm)N0 tumours)

23. HER2+ve ‘Low Risk’ Breast Cancer Key Issues Should women with HER2+ve low risk breast cancer be given CT and trastuzumab? Would women with HER2+ve low risk breast cancer benefit from trastuzumab alone (or with endocrine therapy if ER+ve?) If so would the gain from additional chemotherapy be clinically worthwhile?

24. Anthracyclines – Do we need them in HER2+ pts?

25. Anthracyclines – Do we need them? Increasing concern re potential long term morbidity – cardiac tox/leukeamia risk Adjuvant anthracyclines are effective in patients whose tumors have topo II alpha amplification (7% of total) However, almost all of those tumors have simultaneous amplification of Her2 We now have very effective targeted therapies for these tumors (trastuzumab) (BCIRG 006 - TCH)

26. 26 BCIRG006: DFS and OS

27. 27Smith I et al. Lancet 2007;369:29–36; 2. Rastogi et al. ASCO 2007. Abstract LBA513; 2. Perez et al. ASCO 2007. Abstract 512; 3. Slamon D et al. SABCS 2006;Abstract 52 Cardiotoxicity and trastuzumab: pivotal adjuvant trastuzumab trials CHF, congestive heart failure; LLN, lower limit of normal HERA 1 NSABP B-31 2 NCCTG N9831 2 BCIRG 006 3 Trial Chemo Chemo  H AC  P AC  PH AC  P AC  P  H AC  PH AC  D AC  DH DCarboH Arm >55 LLN (typically >50) Baseline LVEF, % 0.6 3.8 2.5 3.5 1.9 0.4 Severe CHF, % 3 15.9 14 17 18.1 8.6 Contractile dysfunction, %

28. 28 Patients should receive Trastuzumab upfront In the joined analysis 5-7% of patients receiving AC have cardiac dysfunction that they never receive Trastuzumab –15% receive less than 1 year of Herceptin In the BCIRG006, 23 pts in the AC  TH arm never got Herceptin due to unacceptable declines in LVEF following AC

29. Combined Targeted agents in EBC

30. 6 wk break Lapatinib x 7.5 mo Trastuzumab for 1 yr Lapatinib for 1 yr Trastuzumab for 3 mo Trastuzumab 3-weekly + lapatinib for 1 yr 1:1 RANDOMIZATION (N=8000) ALTTO Study Design HER2+ invasive breast cancer Centrally-determined HER2+ Surgery, complete (neo)adjuvant anthracycline-based chemotherapy (approved list) LVEF  50 * * = weekly paclitaxel x 12w; as per investigator’s discretion. PIs. M Piccart, EA Perez

31. Early breast cancer, HER2 +ve (n=3600) Early breast cancer, HER2 +ve (n=3600) BETH: Study design Primary Endpoint: Invasive Disease-Free Survival Randomized, open label trial TCH: docetaxel + carboplatin (q3w x 6 cycles) + Herceptin ® (q3w x 1 year) TH  FEC  H: docetaxel + Herceptin ® (q3w x 3 cycles)  5-FU, epirubicin, and cyclophosphamide (q3w x 3 cycles)  Herceptin ® (q3w x 43 weeks) TH  FEC or TCH + Avastin ® TH  FEC or TCH H + Avastin ® 15 mg/kg/q3wk to complete 1 year H to complete 1 year

32. BEATRICE: BEvacizumab as adjuvant treatment of triple negative breast cancer DFS Triple negative EBC a (n=2530) a HER2− & ER/PgR status confirmed centrally before randomisation; DFS, disease-free survival BEATRICE includes patients with early triple negative breast cancer (basal phenotype) End points –primary end point: disease-free survival –secondary end points: overall survival, recurrence-free survival, distant disease-free survival, time to recurrence, and time to distant recurrence Efficacy and safety follow-up Chemo Chemo + bev (1 year)

33. Are taxane chemotherapy regimens better or worse for “basal-like” cancers? 4162 women (3610 TMA) 800 predicted ER/PR/HER2 -ve Effect of being “Basal-like” “Basal-like” “Triple Negative The Rest The Rest of ER-ve Randomise FEC x 8 or Epi/CMF FEC x 4  Docetaxel x 4 Metastasis Free Survival Formal test of interaction Sub-group and treatment effect Hypothesis taxane resistance 7 IHC markers Nielsen “basal-like” definition Sufficient Power Formal test of interaction HRs UK TACT Adjuvant study P Ellis, P Barrett-Lee, J Bliss S Johnston - Trans-TACT TRICC ER-ve + EGFr And /or CK5/6 P-Cadherin CK14 CK17

34. Neoadjuvant Trastuzumab

35. Neoadjuvant trial in HER2-positive operable BC: pathCR rates 26.3% n=19 65.2 % n=23 25.0% n=16 66.7% n=18 95% CI (41–87%) p=0.02 95% CI (43–84%) p=0.016 (n=34)(n=42) pCR (%) P + FEC alone H + (P  FEC) Buzdar A, et al. Proc ASCO 2004;23:7

36. NOAH study: neoadjuvant Herceptin for LABC a Hormone receptor-positive patients receive adjuvant tamoxifen AP, doxorubicin 60 mg/m 2, paclitaxel 150 mg/m 2 ; H, Herceptin 8 mg/kg loading then 6 mg/kg P, paclitaxel 175 mg/m 2 ; CMF, cyclophosphamide 600 mg/m 2, methotrexate 40 mg/m 2, 5-fluorouracil 600 mg/m 2 LABC, locally advanced breast cancer; q3w, every 3 weeks; q4w, every 4 weeks HER2-positive LABC (IHC 3+ and/or FISH+) n=113 H + AP q3w x 3 H + P q3w x 4 H q3w x 4 + CMF q4w x 3 Surgery followed by radiotherapy a H continued q3w to Week 52 n=115 P q3w x 4 CMF q4w x 3 Surgery followed by radiotherapy a AP q3w x 3 P q3w x 4 CMF q4w x 3 Surgery followed by radiotherapy a n=99 HER2-negative LABC (IHC 0/1+)

37. p=0.002 p=0.004 pCR (%) Baselga et al 2007; Gianni et al 2007 HER2 positive (n=228) HER2 positive (n=62) Neoadjuvant Herceptin significantly improves pCR rates in the NOAH trial Without Herceptin With Herceptin 90 80 70 60 50 40 30 20 10 0 HER2 negative (n=99) HER2 negative (n=14) 234317195529 Total populationIBC population pCR, pathological complete response in the breast IBC, inflammatory breast cancer

38. pCR rate in context: IBC irrespective of HER2 status A, doxorubicin; C, cyclophosphamide; D, docetaxel; E, epirubicin; F, 5-fluorouracil; HD, high-dose 5-fluorouracil (750 mg/m 2 ); SCT, stem cell transplantation Baselga et al 2007, n=31 AT → T → CMF + H FEC-HD FAC or FAC + T ET E →T ET CAF or CEF D + carboplatin (including non-IBC) FAC → mitoxantrone + C + melphalan + SCT Chemotherapy NOAH (trastuzumab) Study pCR (%) Baselga J et al ECCO 2007 Abs O#2030

39. NOAH: cardiac safety LVEF worst value no change absolute decrease ≥10% or <20% absolute decrease ≥20% CHF responsive to treatment + H (n=114) 75 21 2 - H (n=113) 84 15 1 0 87 12 1 0 HER2 positive HER2 negative (n=99) LVEF worst value LVEF, left ventricular ejection fraction Two patients experienced LVEF declines to <45%: one patient during H who withdrew from study and one patient after completing H as per protocol Gianni et al ASCO Breast 2007, Abs 144 Patients %

40. Trastuzumab for EBC has changed approaches to treating breast cancer 1 During the first 10 years, it is predicted that the use of trastuzumab will result in an annual decline in MBC patients of 2.5% 1 Trastuzumab treatment of HER2+ EBC is expected to prevent almost 28,000 women from developing metastases over a 10-year period in five EU countries alone, including the UK, which may result in a similar number of breast cancer deaths being avoided 1 “According to our model, [trastuzumab] will be one of the rare examples of current drugs actually changing the epidemiology of a disease” Weisgerber-Kriegl et al. 2008 1 Adapted from Reference 1 Weisgerber-Kriegl et al. ASCO 2008; Abs 6589

41. Summary Trastuzumab remains the cornerstone of adjuvant systemic therapy 12 months remains current standard but duration question remains important eg HERA 1 v 2 yrs; shorter duration therapy 3-6months being tested Real alternatives to anthracyclines now available –TCH Addition of novel therapeutics (e.g. Bevacizumab, Lapatinib) may offer more patients the potential for cure Adjuvant trastuzumab is changing the natural history of the disease Neoadjuvant trastuzumab promising – safe and effective