Il punto di vista del clinico

Fabio Puglisi, MD PhD

Ruolo della terapia antiangiogenica nel carcinoma mammario

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

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

Goals of Therapy

Maximize survival

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

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

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 + SPPIf the progression eventis death, then SPP = 0

Broglio KR & Berry DA, JNCI 2009

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)

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

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

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

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 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.

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, %

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)

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• 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

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

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

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