1. RUOLO DELLA TERAPIA ANTIANGIOGENICA NEL CARCINOMA MAMMARIO Rilevanza delle Evidenze Scientifiche P Pronzato Modena, 18.11.2011

2. (Anti-) Angiogenesis

3. [TITLE]

5. HER2- Metastatic Breast Cancer (CT Needed) Decision Making Problems

6. F Cardoso & J Cortes

10. MBC: main drivers in 2010s Clinico Pathological Factors – HER2 /HR – Previous Treatment – Burden of Disease

11. MBC: main drivers in 2010s Goals – Prolongation of Survival – Quality of Life – Symptom Relief – Response – Delay of Progression Clinico Pathological Factors – HER2 /HR – Previous Treatment – Burden of Disease

12. MBC HER2 HER2- HER2+ HR+HR- After HT CHEMOTHERAPY Previous anthra-taxanes CT Evidence Based Decision Making HER2- / MBC

13. MBC HER2 HER2- HER2+ HR+HR- After HT CHEMOTHERAPY Previous anthra-taxanes CT Evidence Based Decision Making HER2- / MBC

14. [TITLE] MN Dickler, ASCO 2011

15. RCTs and Meta-Analysis

16. Survival Analyses Miller K et al. N Engl J Med 2007;357:2666-2676

17. Hazard Ratios for Disease Progression Miller K et al. N Engl J Med 2007;357:2666-2676

18. Hazard Ratios for Disease Progression Miller K et al. N Engl J Med 2007;357:2666-2676 Soon this regimen became widely adopted by clinicians who treated thousands of patients and felt confortable with using the drug AM Gonzalez-Angulo, Nat Rev Clin Oncol 2011

19. Trial Design Capecitabine (1000 mg/m 2 bid d1–14) Taxane (docetaxel 75–100 mg/m 2 or nab-paclitaxel 260 mg/m 2 ) Anthracycline-based chemotherapy AC (doxorubicin 50–60 mg/m 2, cyclophosphamide 500–600 mg/m 2 ) EC (epirubicin 90–100 mg/m 2, cyclophosphamide 500–600 mg/m 2 ) FAC (5-FU 500 mg/m 2, doxorubicin 50 mg/m 2, cyclophosphamide 500 mg/m 2 ) FEC (5-FU 500 mg/m 2, epirubicin 90–100 mg/m 2, cyclophosphamide 500 mg/m 2 ) Bevacizumab or placebo (15 mg/kg) Investigator’s choice of chemotherapy Capecitabine or taxane/ anthracycline Previously untreated MBC (n=1237) Stratification factors: Disease-free interval Previous adjuvant chemotherapy No. of metastatic sites Capecitabine, taxane or anthracycline Optional 2nd - line chemotherapy + bevacizumab Treat until PD RANDOMIZE 2:1 Robert et al. ASCO 2009 Chemotherapy + bevacizumab q3w Chemotherapy + placebo q3w NJ Robert, JCO 2011

20. 1.0 0.8 0.6 0.4 0.2 0 IRC assessment Median, months9.86.2 HR (95% CI)*0.68 (0.54–0.86) p=0.0011 Investigator assessment Median, months8.65.7 HR (95% CI)*0.69 (0.56–0.84) p=0.0002 PFS: Capecitabine Cohort BV (n=409) PL (n=206) PFS estimate 0612182430 Months 5.78.6 *Stratified analysis Robert et al. ASCO 2009 NJ Robert, JCO 2011

21. Objective Response Rate*: Capecitabine Cohort Patients, % p=0.0097 *Patients with measurable disease at baseline 23.6 35.4 Complete response Partial response Robert et al. ASCO 2009 NJ Robert, JCO 2011

22. A Meta-Analysis of Overall Survival Data from Three Trials of Bevacizumab and First-Line Chemotherapy as Treatment for Patients with Metastatic Breast Cancer Baylor-Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX; Mount Vernon Cancer Centre, London, England; Dana-Farber Cancer Institute, Boston, MA; Institut Curie, Paris, France; Mayo Clinic, Jacksonville, Florida; Michiana Hematology Oncology, South Bend, IN; Vall d'Hebron University Hospital, Barcelona, Spain; BioOncology, Genentech, S San Francisco, CA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN Joyce O’Shaughnessy, David Miles, Robert Gray, Véronique Diéras, Edith A. Perez, Robin Zon, Javier Cortés, Xian Zhou, See-Chun Phan, Kathy Miller ASCO, 2010

23. 23 General Study Designs Optional Second- line Chemo + BV ( AVADO and RIBBON-1 only ) Chemo + No BV Chemo + BV Treat until PD RANDOMIZE Previously Untreated MBC RIBBON-1 Capecitabine, Taxane, or Anthracycline AVADO Docetaxel E2100 Paclitaxel

24. 24 BV=bevacizumab, PL=placebo, PFS=progression-free survival, ORR=objective response rate, OS=overall survival. * Permitted continuing on BV or crossing over to BV. † Analyses based on IRF assessments. Comparison of the Studies E2100AVADO*RIBBON-1* No. of patients7224881237 GeographyUS (90%)Ex-USUS (50%) Randomization ratio (BV:PL) 1:1 2:1 Chemotherapy Paclitaxel weekly Docetaxel Capecitabine, Docetaxel/nab-Paclitaxel, Doxorubicin/Epirubicin Primary EndpointPFS † PFS Key Secondary Endpoints OS, ORR OS, ORR, 1-yr survival

25. 25 Overview of Efficacy Results from the Individual Studies in the Pooled Analysis E2100AVADO RIBBON-1 (Cape) RIBBON-1 (Tax/Anthra) Non- BV BV Non- BV BV* Non- BV BV Non- BV BV Median PFS, mo 5.811.37.98.85.78.68.09.2 Stratified HR (95% CI) 0.48 (0.39–0.61) 0.62 (0.48–0.79) 0.69 (0.56–0.84) 0.64 (0.52–0.80) p-valuesp<0.0001p=0.0003p=0.0002p<0.0001 BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline. * 15 mg/kg cohort.

26. 26 Patient Characteristics, Pooled Population Non-BV (n  1008) BV (n  1439) Age, median 55 yr56 yr Triple-negative disease, %2625 Disease-free interval (≤24 mo), %3937 Prior adjuvant chemo, %6462 Taxane2224 Anthracycline5248 Visceral disease, %7169 ≥3 metastatic sites, %3841

27. 27 Progression-Free Survival, Pooled Population Non-BV (n=1008) BV (n=1439) Median, mo6.79.2 HR (95% CI)0.64 (0.57–0.71)

28. 28 Analysis of PFS by Subgroups

29. 29 Objective Response Rate* *Includes only patients with measurable disease at baseline. Non-BV (n=788) BV (n=1105) 50 0 45 40 35 30 25 20 15 10 5 32 49 Objective response rate (%)

30. 30 Overall Survival, Pooled Population Non-BV (n=1008) BV (n=1439) Median, mo26.426.7 HR (95% CI)0.97 (0.86–1.08) 1-yr survival rate (%) 7782

31. 31 Use of Subsequent Systemic Therapies in AVADO and RIBBON-1 Studies* % Non-BV (n  654) BV (n  1071) Any chemotherapy7165 Bevacizumab5140 Any hormonal therapy2523 # of subsequent anti-cancer agents ≥42723 31512 22726 11015 *Data not available from E2100.

32. 32 Conclusions Significant PFS advantage but no OS difference with BV across 3 first-line studies and in pooled analysis -In MBC, the ability of Phase III trials to demonstrate treatment effect upon OS depends on the duration of survival post-progression (SPP) -Higher chance of affecting OS in populations with short SPP (20 month PPS in these 3 first-line trials) Patients with adverse prognostic features benefit from BV as do patients with more indolent disease Low incidence of treatment-related deaths with BV Safety profile consistent with previous BV experience Broglio and Berry. 2009. J Natl Cancer Inst. 101:1642-49. Saad, Katz, and Buyse. 2010. J Clin Oncol. 28:1958-62. Burzykowski, et al. 2008. J Clin Oncol. 26:1987-92.

33. A look at TNBC

34. 34 [TITLE]

35. 35 [TITLE]

37. Facts and Prejudices

38. Regrowth Toxicity Age Cost

39. D Miles, JCO 2011 From discontinuation to death

41. V Ranpura, JAMA 2011 Bevacizumab and FAEs

42. V Ranpura, JAMA 2011

43. T Choueiri, JCO 2011 Bevacizumab and CHF

44. 44 Safety, Causes of Death* % Non-BV (n  982) BV (n  1679) Total deaths55.851.3 MBC51.547.4 Treatment-related1.82.1 Other1.41.5 Missing1.00.3 *Safety evaluable patient population.

45. 45 Grade ≥3 Selected Adverse Events (AEs), Pooled Population % Non-BV (n  982) BV (n  1679) Neutropenia7.110.0 Sensory neuropathy8.59.5 Hypertension1.29.0 Febrile neutropenia3.56.5 Venous thromboembolic event3.82.8 Proteinuria02.3 Arterial thromboembolic event0.31.6 Bleeding0.41.5 Left ventricular systolic function0.21.5 Wound dehiscence0.30.8 Fistula0.30.5 GI perforation0.30.5 RPLS0<0.1 RPLS=Reversible posterior leukoencephalopathy syndrome.

46. 46 Grade ≥3 Selected Adverse Events (AEs), Pooled Population % Non-BV (n  982) BV (n  1679) Neutropenia7.110.0 Sensory neuropathy8.59.5 Hypertension1.29.0 Febrile neutropenia3.56.5 Venous thromboembolic event3.82.8 Proteinuria02.3 Arterial thromboembolic event0.31.6 Bleeding0.41.5 Left ventricular systolic funct.0.21.5 Wound dehiscence0.30.8 Fistula0.30.5 GI perforation0.30.5 RPLS0<0.1 RPLS=Reversible posterior leukoencephalopathy syndrome.

47. Elderly Patients X Pivot, EJC 2011

48. TJ Smith, & BE Hillner, NEJM 2011

49. Cost-Effectiveness

50. Conclusions

51. Question 1: Bevacizumab is approved for first line therapy of MBC patients. Is this indication appropriate? Question 2: Do the results of the AVADO (Docetaxel) and/or RIBBOn-1 trials represent a favorable risk-benefit analysis for the upfront therapy of MBC? Question 3:Do the results of the RIBBOn-1 and AVADO trials confirm the Clinical Benefit of Bevacizumab in combination with Paclitaxel for the initial treatment of patients with HER2- MBC? Question 4: Will the PFS time no longer be accepted as an endpoint without QoL data?

52. Conclusions Neo-Angiogenesis is obviously important also in Breast Cancer Addition of Bevacizumab to CT results in a clear advantage in RR and PFS The advantage may be clinically very relevant in some situations (ie TNBC) Toxicity is manageable Age and other factors are little relevant Cost issue should be scientifically faced

53. [TITLE]