Ruolo della terapia antiangiogenica nel carcinoma mammario
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Transcript of Ruolo della terapia antiangiogenica nel carcinoma mammario
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Il punto di vista del clinico
Fabio Puglisi, MD PhD
Ruolo della terapia antiangiogenica nel carcinoma mammario
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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
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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
QUALITYOF LIFE
Overt metastatic disease is generally incurable
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Goals of Therapy
Maximize survival
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Bevacizumab:First-line trials
Efficacy
E-2100 AVADO Ribbon-1 Capecitabine
Ribbon-1
A/TControl
Arm
Beva
Arm
Placebo
Arm
Beva
Arm
7.5/15 mg/kg
Placebo
Arm
Beva
Arm
Placebo
Arm
Beva
Arm
PFS months
5.9 11.8 8.2 9/10.1 5.7 8.6 8.0 9.2
HR0.60
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
25.2 26.7 31.9 30.8/30.3 21.2 29 23.8 25.2
HR0.88
P=.16
1.05/1.03
P=.72/.85
0.85
P=.27
1.03
P=.83
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Endpoints in phase III Metastatic Breast Cancer trials
9/73 (12%) of trialsdemonstrated OSgains
OS gains lessfrequently noted infirst-line trials (8%)than in second-line+trials (22%)
Verma S, et al. The Oncologist 2011Verma S, et al. The Oncologist 2011
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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
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Survival post-progression
OS = PFS + SPPIf the progression eventis death, then SPP = 0
Broglio KR & Berry DA, JNCI 2009
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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)
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Chance of seeing a survival benefit according to SPP
> 90% if SPP = 2 months
< 50% if SPP = 8 months
< 20% if SPP = 24 months
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First-line trials and SPP
Efficacy
E-2100 AVADO Ribbon-1 Capecitabine
Ribbon-1
A/TControl
Arm
Beva
Arm
Placebo
Arm
Beva
Arm
7.5/15 mg/kg
Placebo
Arm
Beva
Arm
Placebo
Arm
Beva
Arm
OS months
25.2 26.7 31.9 30.8/30.3 21.2 29 23.8 25.2
HR0.88
P=.16
1.05/1.03
P=.72/.85
0.85
P=.27
1.03
P=.83
SPP
months19.3 14.9 23.7 21.8/20.2 15.5 20.4 15.8 16
SPP, mos 17.5 19.7 -
Meta-analysis: summary of results
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Meta-Analysis crossover and post-study therapiesTherapies used upon progression in AVADO and
RIBBON-1a
Therapy, %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
15261223
10271527
O’Shaugnessy J et al, ASCO 2010. Abstract 1005aData not available from E2100
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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
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Survival curve percentiles and their corresponding scenarios
Published Ahead of Print on December 28, 2010 as 10.1200/JCO.2010.30.2174
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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)
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The Main Question
Who are these patients, and what characteristics predict for the tail of the
curve?
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Goals of Therapy
Maintain disease control
Minimize symptoms from disease
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Endpoints in Clinical TrialsWhat 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.
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0
20
40
60
80
100
Investigator assessment IRF assessment
aPatients with measurable disease at baseline
Klencke et al. ASCO 2008
Pat
ient
s, %
23%
Paclitaxel Bevacizumab + paclitaxel
48%
p<0.0001
Paclitaxel Bevacizumab + paclitaxel
p<0.0001
E2100: response ratea
0
20
40
60
80
100
22%
50%
Pat
ient
s, %
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0
20
40
60
80
100
aPatients with measurable disease at baseline
Miles et al. SABCS 2009
Pat
ient
s, %
46%
Placebo + docetaxel(n=207)
Bevacizumab 15 mg/kg q3w +
docetaxel(n=206)
64%
p=0.0003
AVADO: Overall Response Ratea (Bevacizumab 15 mg/kg q3w)
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Goals of Therapy
Minimize toxicity from treatment
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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
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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
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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
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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
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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
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To understand the
risk/benefit ratio
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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
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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
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