1. Il punto di vista del clinico Fabio Puglisi, MD PhD Ruolo della terapia antiangiogenica nel carcinoma mammario

2. Therapeutic Options in Metastatic Breast Cancer No single “Gold Standard” for therapy in metastatic breast cancer Therapy should be individualized based on goals, tumor, and patient characteristics

3. Goals of Therapy Judicious use of agents individualized to the patient’s clinical situation Maximize survival Maintain disease control Minimize symptoms from disease Minimize toxicity from treatment QUALITY OF LIFE Overt metastatic disease is generally incurable

4. Goals of Therapy Maximize survival

5. Bevacizumab:First-line trials Efficacy E-2100AVADO Ribbon-1 Capecitabine Ribbon-1 A/T Control Arm Beva Arm Placebo Arm Beva Arm 7.5/15 mg/kg Placebo Arm Beva Arm Placebo Arm Beva Arm PFS months 5.911.88.29/10.15.78.68.09.2 HR 0.60 P<.0001 0.86 P=.12 (7.5 mg) 0.77 P=.006 (15 mg) 0.69 P=.0002 0.64 P<.0001 OS months 25.226.731.930.8/30.321.22923.825.2 HR 0.88 P=.16 1.05/1.03 P=.72/.85 0.85 P=.27 1.03 P=.83

6. Endpoints in phase III Metastatic Breast Cancer trials 9/73 (12%) of trials demonstrated OS gains OS gains less frequently noted in first-line trials (8%) than in second-line+ trials (22%) Verma S, et al. The Oncologist 2011

7. Why OS gain is rarely noted? Potentially active subsequent lines (including crossover) are not controlled in most RcTs Many RcTs lack statistical power to detect plausible increases in OS Larger sample size is requested Longer follow-up period is requested

8. Survival post-progression OS = PFS + SPP If the progression event is death, then SPP = 0 Broglio KR & Berry DA, JNCI 2009

9. Broglio, K. R. et al. J. Natl. Cancer Inst. 2009 Probability of statistically significant differences in overall survival (OS) as a function of median survival postprogression (SPP)

10. Chance of seeing a survival benefit according to SPP > 90% if SPP = 2 months < 50% if SPP = 8 months < 20% if SPP = 24 months

11. First-line trials and SPP Efficacy E-2100AVADO Ribbon-1 Capecitabine Ribbon-1 A/T Control Arm Beva Arm Placebo Arm Beva Arm 7.5/15 mg/kg Placebo Arm Beva Arm Placebo Arm Beva Arm OS months 25.226.731.930.8/30.321.22923.825.2 HR 0.88 P=.16 1.05/1.03 P=.72/.85 0.85 P=.27 1.03 P=.83 SPP months 19.314.923.721.8/20.215.520.415.816 SPP, mos17.519.7- Meta-analysis: summary of results

12. Meta-Analysis crossover and post-study therapies Therapies used upon progression in AVADO and RIBBON-1 a Therapy, % CT + Beva (n=1071) CT (n=654) Chemotherapy6571 Bevacizumab4051 Hormonal therapy2325 Number of subsequent agents – 1 – 2 – 3 – ≥ 4 15 26 12 23 10 27 15 27 O’Shaugnessy J et al, ASCO 2010. Abstract 1005 a Data not available from E2100

13. Estimating scenarios for survival 36 first-line chemotherapy trials for metastatic breast cancer published from 1999 to 2009 –Mean for Median PFS: 7.6 months (6.0-9.0) –Mean for Median SPP: 14 months (10.8-15.6) –Mean for Median OS: 21.7 (18.2-24.0) –Mean for Median ratio OS/PFS: 3 (2.4-3.5) –Mean 1-year survival: 73% (69-78%) –Mean 2-year survival: 45% (38-50%) –Mean 5-year survival*: 12% (7-17%) *information available only in 14 trials Published Ahead of Print on December 28, 2010 as 10.1200/JCO.2010.30.2174

14. Survival curve percentiles and their corresponding scenarios Published Ahead of Print on December 28, 2010 as 10.1200/JCO.2010.30.2174

15. Simple rules of thumb: bevacizumab Estimates by multiplying median by four simple multiples: 0.25 (worst-case)  0.25 x 26.7 = 6.67 0.5 (lower-typical)  2 (upper-typical)  0.5 x 26.7 = 13.3  2 X 26.7 = 53.4 3 (best-case)  3 x 26.7 = 80.1 (= 6.7 years)

16. The Main Question Who are these patients, and what characteristics predict for the tail of the curve?

17. Goals of Therapy Maintain disease control Minimize symptoms from disease

18. Endpoints in Clinical Trials What Matters Most? Progression-free survival and response rate are important achievements in their own right –Shrinking a cancer may minimize a patient's acute symptoms. –Prolonging progression-free survival may be associated with enhanced quality of life, even without an improvement in overall survival.

19. Investigator assessmentIRF assessment a Patients with measurable disease at baseline Klencke et al. ASCO 2008 Patients, % 23% PaclitaxelBevacizumab + paclitaxel 48% p<0.0001 PaclitaxelBevacizumab + paclitaxel p<0.0001 E2100: response rate a 22% 50% Patients, %

20. a Patients with measurable disease at baseline Miles et al. SABCS 2009 Patients, % 46% Placebo + docetaxel (n=207) Bevacizumab 15 mg/kg q3w + docetaxel (n=206) 64% p=0.0003 AVADO: Overall Response Rate a (Bevacizumab 15 mg/kg q3w)

21. Goals of Therapy Minimize toxicity from treatment

22. Bleeding/hemorrage Serious hemorragic events (grade ≥ 3) were uncommon ≤ 1.7% of patients in the bevacizumab arms (only in the taxane-BV arm of RIBBON-1: 5.4%) Trials allowed use of anticoagulants and aspirin Exploratory analysis of AVADO data –No CNS bleeding events in pts who developed brain metastases while on study Hamilton EP & Blackwell KI. Oncology 2011; 80: 314-25

23. Wound-healing complications Incidence of grade 3 or 4 wound-healing complications ≤ 1.5% of patients in the bevacizumab arms ≤ 1% of patients in the control arms Interval between bevacizumab administration and elective surgery –Based on 20-day half-life –Do not administer bevacizumab at least 4 weeks before and 4 weeks after surgery Hamilton EP & Blackwell KI. Oncology 2011; 80: 314-25

24. Thromboembolic events Arterial thrombotic events –Twice as frequently in patients treated with bevacizumab 3.8% vs. 1.7% (meta-analysis of trials in mCRC, MBC, NSCLC) No increased risk for venous thromboembolic events Hamilton EP & Blackwell KI. Oncology 2011; 80: 314-25

25. When Meta-analyses add little to our body of evidence: Bevacizumab and Heart Failure Risk Retrospectively collected heart failure data Lack of information about individual patients No information about underlying risk factors –Cumulative anthracycline dose –Prior radiation –Atherosclerotic disease –Hypertension/Diabetes/Obesity Lack of accurate definition of heart failure –Heart failure is not equilavent to cardiomyopathy or to left ventricular dysfunction Verma & Swain, J Clin Oncol 2011 TRIALS –Miller JCO 2005 –E2100 –AVADO –RIBBON-1 –RIBBON-2 Bevacizumab in pts with MBC increase the risk of G3-4 CHF five-fold with an overall incidence of 1.6% (vs 0.4% in the control/placebo group) Choueri, J Clin Oncol 2011

26. Cardiovascular events RIBBON-1 is the only phase III trial including a prospective cardiac evaluation –No significant increase of grade ≥ 2 left ventricular systolic dysfunction when bevacizumab was combined with anthracyclines 6.2% vs. 6%, respectively, at the primary data cut Robert NJ, et al. J Clin Oncol 2011

27. To understand the risk/benefit ratio

28. Clinical benefit and molecular heterogeneity of breast cancer ORR/PFS Survival unselected population Predictors of response/PFS may not predict OS in unselected cases A single predictive biomarker cannot fit all tumor types

29. Clinical benefit and molecular heterogeneity of breast cancer Population A Population C Population B ORR/PFS Survival unselected population Predictors of response/PFS may not predict OS in unselected cases A single predictive biomarker cannot fit all tumor types chemotherapy