1. Adjuvant therapy of HER2 positive early breast cancer The Evidences Antonio Frassoldati Oncologia Clinica - Ferrara

2. Evidences on adjuvant trastuzumab are based on randomized trials in over 14,000 women TrialPt. N.Trastuz.DurationMedian FUPublished results B31/N98313351C+S1 y48 mosY N98313046S or C+S1 y72 mosY* HERA5090S1 or 2 y48 mosY BCIRG0063222C+S1 y65 mosY FinHER232C3 m62 mosY PACS-04528S1y47 mosY S= sequential; C= concomitant * Early release after second interim analysis (arm A, B) and first interim analysis (arm B,C)

3. Main trial designs of adjuvant Trastuzumab NSABP B-31 Node positive N9831 Node pos/neg HR Paclitaxel q3w x 4 Paclitaxel x 4, H qw x 52 AC q3w x 4 H qw x 52 Paclitaxel qw x 12 Paclitaxel qw x 12, H qw x 52 AC q3w x 4 BCIRG 006 Node pos/neg HR Docetaxel q3w x 4 AC q3w x 4 H qw x 12, q3w † x 14 Docetaxel q3w x 4 Carboplatin + Docetaxel q3w † x 6 H qw x 18, q3w x 12 HERA Chemotherapy (any) Node pos/neg HR Chemotherapy (any)  H qw x 52 Chemotherapy (any)  H qw x 104

4. Main research questions in trials of adjuvant trastuzumab Does trastuzumab reduce the rate of recurrence (and death)? (All) Does the schedule of trastuzumab administration matter? (N9831, BCIRG006) Does the duration of trastuzumab matter? (HERA) Does the chemotherapy regimen influence the activity and safety of trastuzumab? (BCIRG006)

5. Cross-comparison among the trials of adjuvant trastuzuamb TrialPt. N.Primary endpoint Crossover B31/N98313351DFS15% N98313046DFSY HERA°5090DFS52% BCIRG0063222DFS2.1% FinHER232DFSN PACS04528DFSN ° Pts in HERA trial were randomized after the end of adjuvant therapy

6. B31/N9831 Efficacy results Perez, JCO 2011 Relapse HR 0.52 (0.45-0.60)

7. B31/N9831 Efficacy results Perez, JCO 2011 Death HR 0.61 (0.50-0.75)

8. No. of deaths H 1 year vs. observation 012 Favours trastuzumab Favours no trastuzumab HR OS benefit 29 vs. 37 p=0.26 2005 1 1 year (0%) 59 vs. 90 p=0.0115 182 vs. 213 p=0.1087 Median follow-up (% follow-up time after selective crossover) 2006 2 2 years (4.1%) 2008 3 4 years (30.9%) 2005 1 1 year (0%) Median follow-up (% follow-up time after selective crossover) 2006 2 2 years (4.3%) 2008 3 4 years (33.8%) No. of DFS events H 1 year vs. observation 127 vs. 220 p<0.0001 218 vs. 321 p<0.0001 369 vs. 458 p<0.0001 012 Favours trastuzumab Favours no trastuzumab HR DFS benefit 1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011 HERA: DFS and overall survival over time

9. HERA - Observation patients by status on 16 May 2005 1698 patients originally randomised to observation 1354 patients alive and disease free 16 May 2005 344 patients DFS event or lost to follow-up 198 alive post DFS event 469 patients remained on observation 344 patients ineligible for crossover Gianni, Lancet Oncol 2011 885 patients crossed over to trastuzumab

10. HERA - DFS (landmark analysis): selective crossover and no crossover 100 80 60 40 20 0 0 Months from randomisation No. at risk Patients alive and disease free (%) Selective crossover* No crossover 612182430364248 885 884878870851822690480 469468455438408388358302232 HR 0.68 (0.51-0.90) p=0.0077 Gianni, Lancet Oncol 2011 * Median time to start trastuzumab: 22.8 mos (4.5-52.7)

11. N9831 Efficacy results Sequential vs Concomitant + sequential Perez, JCO 2011

12. BCIRG006 Efficacy results Slamon, NEJM 2011 DFS HR AC-TH vs AC-T 0.64 TCH vs AC- T 0.75

13. FinHER Efficacy results Joensuu, JCO 2009

14. Efficacy of adjuvant trastuzuamb on Survival Trial HRMedian FU B31/N9831 0.6148 mos N9831 AC-T vs AC-T-H AC-T-H vs AC-TH-H 0.88 0.78 72 mos HERA° 0.8548 mos BCIRG006 AC-T vs AC-TH-H AC-T vs TCH 0.63 0.77 65 mos FinHER 0.5562 mos ° ITT, not adjusted for selective crossover

15. Efficacy in subgroups ER and Nodal status Slamon, NEJM 2011 AC-TH-H TCH

16. Time-dependent Hazard Rate for recurrence by hormone receptor status ER positive ER negative Untch, Ann Oncol 2008 HERA trial

17. Efficacy in subgroups Small tumors Gonzalez-Angulo, JCO 2009 MDACC 965 pT1a-b N0 Hazard Ratio for recurrence 5.3 97.2% 86.4%

18. Efficacy in subgroups Small tumors Slamon, NEJM 2011 BCIRG006

19. Efficacy in subgroups Topo2A status Slamon, NEJM 2011 With Topo2A coamplification Without Topo2A coamplification

20. Cardiac safety TrialNot starting trastuzuamb Trastuz. Discontin. Cardiac dysfunction° CHF B31/N98314.3%17.3% 320/1845 3.8% N9831 (C+S)2.8%19%9.1% 87/949 2.2% HERA--5.2%3.7%0.8% BCIRG006 AC-TH 2.1%n.r. AC-TH 18.6% TCH 9.4% AC-TH 2.0% TCH 0.4% FinHER--4-7% of doses 3.9%*0.9% * ° >10 points relative reduction in LVEF *after CT

21. 0.00 Suter et al 2007 a Median follow-up 12 months; DFS, disease-free survival Obs; any cardiac end point H; any cardiac end point Obs; DFS events H; DFS events 6121824 Months a 0.05 0.10 0.15 0.20 0.25 Probability No. at risk Observation Trastuzumab 16931106784455226 1693 1139861520260 0 HERA: risk-benefit ratio with adjuvant trastuzumab a

22. Cardiac outcomes after any type of cardiac endpoint Trastuzumab patients who have any type of CE (n=73) Trastuzumab patients who reached acute recovery after any type of CE (n=59) Trastuzumab patients who had a further LVEF drop to <50% (n=59) 19.2% 80.8% 71.2% 28.8% 35.3% 64.7%

23. Duration of Trastuzumab TrialDuration in months CT regimenNo. of pts HERA (BIG) 12 vs. 24Center’s choice 3,387 PHARE (France) 6 vs. 12Center’s choice 3,400 PERSEPHONE (UK) 6 vs. 12Center’s choice 4,000 SHORTER (Italy) 3 vs.12A+T vs. T+FEC 1,500 SOLD (Finland & BCG) 3 vs 12T+FEC3,000

24. Adjuvant HER2- directed Therapy Questions to be solved: – Indication for the better regimen for combination with trastuzumab (Anthracycline/taxane or docetaxel/carboplatin) – Role of shorter trastuzumab regimens – Treatment of triple-positive tumor migth avoid chemotherapy, particularly on small tumors (T1a,b N0) – Prediction of response to individual HER2-directed agents – Role of dual HER2 inhibition

25. Double inhibition of HER2

26. Trastuzumab clearly changed the prognosis of HER2 breast cancer patients. Several new ways for further improvements can now to be explored HER2 street