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Ruolo della terapia antiangiogenica nel carcinoma mammario Il punto di vista del clinico Fabio Puglisi, MD PhD 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 Goals of Therapy Overt metastatic disease is generally incurable 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 Goals of Therapy Maximize survival Bevacizumab:First-line trials E-2100 Efficacy PFS months HR OS months HR AVADO 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 5.9 11.8 8.2 9/10.1 5.7 8.6 8.0 9.2 0.60 P<.0001 25.2 26.7 0.88 P=.16 0.86 P=.12 (7.5 mg) 0.77 P=.006 (15 mg) 31.9 30.8/30.3 1.05/1.03 P=.72/.85 0.69 P=.0002 21.2 0.85 P=.27 29 0.64 P<.0001 23.8 25.2 1.03 P=.83 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 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 Survival post-progression OS = PFS + SPP If the progression event is death, then SPP = 0 Broglio KR & Berry DA, JNCI 2009 Probability of statistically significant differences in overall survival (OS) as a function of median survival postprogression (SPP) Broglio, K. R. et al. J. Natl. Cancer Inst. 2009 Chance of seeing a survival benefit according to SPP > 90% if SPP = 2 months < 50% if SPP = 8 months < 20% if SPP = 24 months First-line trials and SPP E-2100 Efficacy AVADO Ribbon-1 Capecitabine Control Arm Beva Arm Placebo Arm Beva Arm 7.5/15 mg/kg Placebo Arm Beva Arm 25.2 26.7 31.9 30.8/30.3 21.2 29 OS months 0.88 P=.16 HR SPP months 19.3 1.05/1.03 P=.72/.85 14.9 23.7 21.8/20.2 0.85 P=.27 15.5 Ribbon-1 A/T 23.8 25.2 1.03 P=.83 20.4 15.8 Meta-analysis: summary of results SPP, mos 17.5 19.7 Beva Arm Placebo Arm - 16 Meta-Analysis crossover and post-study therapies Therapies used upon progression in AVADO and RIBBON-1a CT + Beva (n=1071) CT (n=654) Chemotherapy 65 71 Bevacizumab 40 51 Hormonal therapy 23 25 Number of subsequent agents –1 –2 –3 –≥4 15 26 12 23 10 27 15 27 Therapy, % aData not available from E2100 O’Shaugnessy J et al, ASCO 2010. Abstract 1005 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 Survival curve percentiles and their corresponding scenarios Published Ahead of Print on December 28, 2010 as 10.1200/JCO.2010.30.2174 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) The Main Question Who are these patients, and what characteristics predict for the tail of the curve? Goals of Therapy Maintain disease control Minimize symptoms from disease 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. E2100: response ratea Investigator assessment IRF assessment 100 100 80 80 p<0.0001 60 48% 40 Patients, % Patients, % p<0.0001 60 40 23% aPatients 22% 20 20 0 0 Paclitaxel 50% Bevacizumab + paclitaxel with measurable disease at baseline Klencke et al. ASCO 2008 Paclitaxel Bevacizumab + paclitaxel AVADO: Overall Response Ratea (Bevacizumab 15 mg/kg q3w) 100 p=0.0003 Patients, % 80 64% 60 46% 40 20 0 Placebo + docetaxel (n=207) aPatients with measurable disease at baseline Miles et al. SABCS 2009 Bevacizumab 15 mg/kg q3w + docetaxel (n=206) Goals of Therapy Minimize toxicity from treatment 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 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 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 When Meta-analyses add little to our body of evidence: Bevacizumab and Heart Failure Risk • 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 • 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 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 To understand the risk/benefit ratio Clinical benefit and molecular heterogeneity of breast cancer unselected population ORR/PFS Survival • Predictors of response/PFS may not predict OS in unselected cases • A single predictive biomarker cannot fit all tumor types Clinical benefit and molecular heterogeneity of breast cancer unselected population Population A Population C ORR/PFS Survival Population B • Predictors of response/PFS may not predict OS in unselected cases • A single predictive biomarker cannot fit all tumor types