ΑΡΧΕΣ ΣΥΣΤΗΜΑΤΙΚΗΣ ΘΕΡΑΠΕΙΑΣ ΣΤΟΝ ΚΑΡΚΙΝΟ ΜΑΣΤΟΥ

1. ΑΡΧΕΣ ΣΥΣΤΗΜΑΤΙΚΗΣ ΘΕΡΑΠΕΙΑΣ ΣΤΟΝ ΚΑΡΚΙΝΟ ΜΑΣΤΟΥ ΧΑΡΑΛΑΜΠΟΣ ΚΑΛΟΦΩΝΟΣ

4. Treatment algorithm for MBC MBC HR + HR – BRCA mutated HER2+ HER2+ HER2– HER2– SERM SERD AI OFS Trastuzumab + anastrozole (lapatinib + letrozole) PolychemoRx Paclitaxel + Beva DNA damaging CT Olaparib Trastuzumab + taxanes ChemoRx +PARPi Paclitaxel + Beva Single agent chemo Lapatinib + capecitabine Trastuzumab+ capecitabine TDM-1, Pertuzumab, Neratinib, mTORi Metastatic Bone Disease: Bisphosphonates Denosumab

7. ΠΡΩΙΜΟΣ ΚΑΡΚΙΝΟΣ ΜΑΣΤΟΥ Ο πρωτεύων στόχος είναι η πρόληψη της υποτροπής Το όφελος της ταμοξιφαίνης είναι τεκμηριωμένο Ωστόσο, τα ποσοστά των υποτροπών είναι >2% ετησίως και >30%των γυναικών αναπτύσσουν υποτροπιάζουσα νόσο εντός 15 ετών1 1EBCTCG overview. Lancet 2005; 365: 1687-1717

8. Recurrence Lancet 2011; 378: 771–84

10. Lancet Oncol. 2010 Dec;11(12):1135-41

11. Absolute Difference 4.3% Absolute Difference 2.7% TTR Hormone-receptor-positive patients HR 0.79, p=0.0002 Lancet Oncol. 2010 Dec;11(12):1135-41

12. J Clin Oncol 2010;28:3411-3415

13. ATAC : Fracture rates in the full study population Lancet Oncol. 2010 Dec;11(12):1135-41

16. Το denosumab αύξησε σημαντικά την BMD της οσφυϊκής μοίρας της σπονδυλικής στήλης έναντι του εικονικού φαρμάκου Εικ. φάρμακο (n=122) Denosumab (n=123) 8 * 7 * 6 5 * 4 * 3 Εκατοστιαία μεταβολή από την έναρξη της μελέτης (± 95% CI) διαφορά 5,5% στους 12 μήνες διαφορά 7,6% στους 24 μήνες * 2 1 0 -1 -2 -3 1 3 6 12 24 Μήνες * P<0,0001 έναντι εικονικού φαρμάκου Ellis, et al. J Clin Oncol 2008;26:4875-82.

22. There are four receptors in the HER family Receptors are able to homo- and heterodimerise HER2 does not appear to have a direct ligand HER1/EGFR HER2 HER3 HER4 EGFR, epidermal growth factor receptor Yarden & Sliwkowski. Nat Rev Mol Cell Biol 2001;2:127–137

23. HER dimers initiate mitogenic signalling + + + + + + + + + + + + + + + + Homodimers Heterodimers HER1:HER2 HER1:HER3 HER4:HER4 HER1:HER4 HER3:HER3 HER2:HER3 HER2:HER2 HER2:HER4 HER1:HER1 HER3:HER4 + Signalling activity Tzahar et al. Mol Cell Biol 1996;16:5276–5287; Citri et al. Exp Cell Res 2003;284:54–65; Huang et al. Cancer Res 2010;70:1204–1214

24. Trastuzumab targets HER2 andLapatinib targets both EGFR and HER2 The HER2 gene is localized to chromosome 17q HER2 and EGFR are tyrosine kinase transmembrane growth factor receptors Fernandes et al, Cancer Lett 1999; Moghal et al, Curr Opin Cell Biol 1999; Yarden et al, Nat Rev Mol Cell Biol 2001

25. Trastuzumab: Μηχανισμοί δράσης

26. Trastuzumab consistently demonstratesbenefits across multiple lines of treatment EBC MBC Adjuvant Neo 1st line 2nd+ lines Surgery Relapse Progression HERA NSABP-B31 NCCTG N9831 BCIRG 006 HO648g M77001 US Oncology BCIRG 007 CHAT TRAVIOTA TAnDEM Numerous Phase II studies NOAH MDACC Neo-ALTTO EBC, early breast cancer; MBC, metastatic breast cancer

27. Trastuzumab + Chemotherapy improves OS (HER2 IHC 3+ ) Probabilityof survival 1.0 Trastuzumab + chemo Chemotherapy alone 0.9 0.8 0.7 0.6 0.5 0.4 0.3 p<0.05 0.2 0.1 20 months 29 months 0.0 0 5 10 15 20 25 30 35 40 45 50 Time (months) IHC, immunohistochemistry Slamon et al 2001

28. Adjuvant Trastuzumab Trials NSABP-B31 HERA 4 x T 175 mg/m2 4 x AC Observation HER2+(IHC or FISH) HER2+ (IHC or FISH) 1 year Herceptin Accepted chemotherapy:AC, EC, FAC, FEC, ET, AT,CMF 2 years Herceptin 1 year Herceptin BCIRG 006 NCCTG N9831 4 x AC 4 x docetaxel 60/600 mg/m2 100 mg/m2 12 x T 90 mg/m2 4 x AC AC T HER2+(FISH)n=3222 HER2+(IHC or FISH) AC TH 1 year Herceptin 6 xdocetaxel and platinum salts 75 mg/m2 75 mg/m2 or AUC 6 TCarboH 1 year Herceptin 1 year Herceptin IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation; AC, doxorubicin + cyclophosphamide; T, paclitaxel; Carbo, carboplatin

29. HERA: DFS at 4 years of follow-up Gianni L, et al. 2011 6 12 18 24 30 36 42 48 0 DFS benefit of trastuzumab vs observation maintained at 4 years 100 Trastuzumab 1 year 80 6.4% Observation 60 Alive and disease free (%) 40 4-yearDFS 78.672.2 Events 369458 HR 0.76 95% CI 0.66−0.87 P value <0.0001 20 0 Months from randomisation No. at risk 1703 1698 16191564 15521440 14851363 1414 1297 13521240 12801180 1020992 854712

30. HERA: Adverse events and cardiac endpoints Low incidence of cardiac adverse events with trastuzumab *Crossover patients were censored from the date of starting trastuzumab; †Not including cardiac death ‡20 New York Heart Association II and 13 New York Heart Association III and IV § Asymptomatic or mildly symptomatic Gianni L, et al. 2011

31. NCCTG and NSABP Combined analysis: DFS at 4 years of follow-up 100 80 60 40 20 0 0 1 2 3 4 5 Significant DFS benefit of trastuzumab at all timepoints 92.4% 88.0% 85.7% ACTH 86.8% 79.0% ACT 73.7% Alive and disease-free (%) Stratified HR at 4 years = 0.52 (95% CI: 0.45‒0.60); P<0.001 Factors: nodes, hormone receptor status, paclitaxel schedule, study 1952 1756 1300 891 495 No.at risk 1881 1652 1132 702 395 Follow-up (years) Perez EA, et al. 2011

32. DFS and OS: Summary of findings 1. Gianni L, et al. 2011; 2. Slamon D, et al. 2009; 3. Perez EA, et al. 2011

33. Low incidence of cardiac events across studies 10 8 6 4 2 0 Cumulative incidence of cardiac events* with 1 yearof trastuzumab remains low with long-term follow-up NSABP B-31 ACTH (n=947)1 NCCTG N9831 ACTH (n=570)2 NCCTG N9831 ACTH (n=710)2 BCIRG 006 ACTH (n=1068)3 HERA CTH (n=1682)4 Cumulative incidence (%) BCIRG 006 TCH (n=1056)3 3.8% 3.3% 2.8% 2% 0.8% 0.4% 0 1 2 3 4 5 Time (years) *Cardiac events: CHF or cardiac death 1. Rastogi P, et al. 2007; 2. Perez EA, et al. 2008 3. Slamon D, et al. 2009; 4. Procter M, et al. 2010

34. Conclusions DFS and OS benefits with trastuzumab are maintained at long-term follow-up Trastuzumab may be administered either concurrently or sequentially with chemotherapy Trastuzumab is well tolerated with a consistent safety and tolerability profile Incidence of cardiac events remains low Trastuzumab for 1 year for patients with HER2-positive EBC

35. Neoadjuvant Trastuzumab doubles the pathological response rates P=0.002 Patients (%) 50 p=0.003 43 40 38 p=0.29 30 p=0.43 23 20 20 17 16 10 0 With H Without H HER2 negative With H Without H HER2 negative HER2 positive HER2 positive pCR tpCR Eierman et al, 2008 tpCR, total pCR in breast and nodes

36. EFS: HER2-positive population Probability, EFS 1.00 0.75 0.50 95% CI 0.36-0.85 pa 0.006 Events 3652 Patients 115112 HRa 0.56 0.25 H + CTCT 0.00 0 6 12 18 24 30 36 42 Months Median follow-up is 3 years aUnadjusted for stratification variables: adjusted HR=0.55, p=0.0062HR, hazard ratio; CI, confidence interval; CT, chemotherapy

37. Neo-ALTTO: Study DesignThe Lancet, 2012 Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF  50% N=450 lapatinib lapatinib paclitaxel R A N D O M I Z E S U R GE R Y FEC X 3 trastuzumab trastuzumab paclitaxel • Stratification: • T ≤ 5 cm vs. T > 5 cm • ER or PgR + vs. • ER & PgR – • N 0-1 vs. N ≥ 2 • Conservative surgery • or not lapatinib lapatinib trastuzumab trastuzumab paclitaxel + 12 wks 6 wks 34 weeks 52weeks of anti-HER2 therapy

38. Neo-ALTTO: Efficacy – pCR and tpCRThe Lancet, 2012 L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pCR pathologic complete response

39. Conclusions • Primary objective was achieved for the combination arm: 51.3% pCR rate (L+T) was significantly higher than 29.5% (T) • There was an increased toxicity, but manageable, observed in the lapatinib arms (diarrhea and liver enzyme alterations)

40. FutureDirections

41. Complementary modes of actionHerceptin and pertuzumab bind to distinct epitopeson HER2 extracellular domain Herceptin Pertuzumab • Activates antibody-dependent cellular cytotoxicity • Enhances HER2 internalisation • Inhibits shedding and, thus, formation of p95 • Inhibits HER2-regulated angiogenesis • Prevents receptor dimerisation • Activates antibody-dependent cellular cytotoxicity • Potent inhibitor of HER-mediated signalling pathways Hubbard S, et al. Cancer Cell 2005;7:287–8

42. Overall survival: Predefined interim analysisMedian follow-up: 19.3 months, n = 165 OS events Baselga et al SABCS 2011 100 90 80 70 HR = 0.64*95% CI 0.47‒0.88p = 0.0053* 60 50 Overall survival (%) 40 30 Pertuzumab + Trast + Doc: 69 events 20 Placebo + Trast + Doc: 96 events 10 0 0 5 10 15 20 25 30 35 40 45 Time (months) n at risk Pertuzumab + T + D 406 383 347 228 143 67 24 2 0 0 Placebo + T + D 402 387 367 251 161 87 31 4 0 0 * The interim OS analysis did not cross the pre-specified O’Brien-Fleming stopping boundary (HR ≤0.603; p ≤0.0012)

43. T-DM1 MOA • Trastuzumab component binds to HER2 and leads to downstream signaling inhibition/blockade • Targeted intracellular delivery of a potent antimicrotubule agent, DM1 T-DM1 binds to the HER2 protein on tumor cells Intracellular signaling Intracellular signaling inhibition/blockade Receptor-T-DM1 complex is internalized and trastuzumab degrades, leaving the intracellularly active lysine-MCC-DM1 to be released Potent antimicrotubule agent is released inside the HER2-positivetumor cell

46. EMILIA study design T-DM1 3.6 mg/kg q3w IV • HER2+ (central) LABC or MBC (N=980) • Prior taxane and trastuzumab • Progression on metastatic tx or within 6 mos of adjuvant tx PD 1:1 Capecitabine 1000 mg/m2 orally bid, days 1–14, q3w + Lapatinib 1250 mg/day orally qd PD • Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease • Primary end points: PFS by independent review, OS, and safety • Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression Blackwell et al ASCO 2012

47. Progression-free survival by independent review 1.0 0.8 0.6 0.4 Proportion progression-free 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (mos) No. at risk by independent review: Cap + Lap 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 Unstratified HR=0.66 (P<0.0001). Blackwell et al ASCO 2012

48. The Revolution of Molecular Targeted Cancer Therapy Trastuzumab Pertuzumab Lapatinib TDM-1 Ben-Kasus et al., Molecular Oncology