RUOLO DELLA TERAPIA ANTIANGIOGENICA NEL CARCINOMA MAMMARIO

Rilevanza delle Evidenze Scientifiche

P PronzatoModena, 18.11.2011

(Anti-) Angiogenesis

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HER2- Metastatic Breast Cancer(CT Needed)

Decision Making Problems

F Cardoso & J Cortes

F Cardoso & J Cortes

F Cardoso & J Cortes

F Cardoso & J Cortes

MBC: main drivers in 2010s

• Clinico Pathological Factors– HER2 /HR– Previous Treatment– Burden of Disease

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

MBC

HER2 HER2-

HER2+ HR+ HR-

After HT CHEMOTHERAPY

Previous anthra-taxanes CT

Evidence Based Decision MakingHER2- / MBC

MBC

HER2 HER2-

HER2+ HR+ HR-

After HT CHEMOTHERAPY

Previous anthra-taxanes CT

Evidence Based Decision MakingHER2- / MBC

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MN Dickler, ASCO 2011

RCTs and Meta-Analysis

Survival Analyses

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

Hazard Ratios for Disease Progression

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

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

Trial Design

• Capecitabine (1000 mg/m2 bid d1–14)

• Taxane (docetaxel 75–100 mg/m2 or nab-paclitaxel 260 mg/m2)

• Anthracycline-based chemotherapy • AC (doxorubicin 50–60 mg/m2, cyclophosphamide 500–600 mg/m2)

• EC (epirubicin 90–100 mg/m2, cyclophosphamide 500–600 mg/m2)

• FAC (5-FU 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2)

• FEC (5-FU 500 mg/m2, epirubicin 90–100 mg/m2, cyclophosphamide 500 mg/m2)

• 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 adjuvantchemotherapy

•No. of metastatic sites

•Capecitabine, taxane or anthracycline

Optional2nd-line

chemotherapy+

bevacizumab

Treat untilPD

RA

ND

OM

IZE

2:1

Robert et al. ASCO 2009

Chemotherapy +bevacizumab

q3w

Chemotherapy +placebo

q3w

NJ Robert, JCO 2011

1.0

0.8

0.6

0.4

0.2

0

IRC assessment

Median, months 9.8 6.2

HR (95% CI)* 0.68 (0.54–0.86)

p=0.0011

Investigator assessment

Median, months 8.6 5.7

HR (95% CI)* 0.69 (0.56–0.84)

p=0.0002

PFS: Capecitabine Cohort

BV(n=409)

PL(n=206)

PF

S e

stim

ate

0 6 12 18 2430 Months

5.7 8.6

*Stratified analysis Robert et al. ASCO 2009NJ Robert, JCO 2011

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 2009NJ Robert, JCO 2011NJ Robert, JCO 2011

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

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General Study Designs

OptionalSecond-

line Chemo +

BV(AVADO and

RIBBON-1 only)

Chemo +No BV

Chemo +BV

Treat untilPD

RA

ND

OM

IZE

Previously Untreated

MBC

RIBBON-1Capecitabine,

Taxane,or

Anthracycline

AVADODocetaxel

E2100Paclitaxel

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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

E2100 AVADO* RIBBON-1*

No. of patients 722 488 1237

Geography US (90%) Ex-US US (50%)

Randomization ratio (BV:PL)

1:1 1:1 2:1

ChemotherapyPaclitaxel

weeklyDocetaxel

Capecitabine,Docetaxel/nab-Paclitaxel,

Doxorubicin/Epirubicin

Primary Endpoint PFS† PFS PFS

Key Secondary Endpoints

OS, ORROS, ORR,

1-yr survivalOS, ORR,

1-yr survival

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Overview of Efficacy Results from the Individual Studies in the Pooled Analysis

E2100 AVADORIBBON-1

(Cape)RIBBON-1

(Tax/Anthra)

Non-BV

BVNon-BV

BV*Non-BV BV

Non-BV BV

Median PFS, mo

5.8 11.3 7.9 8.8 5.7 8.6 8.0 9.2

StratifiedHR (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-values p<0.0001 p=0.0003 p=0.0002 p<0.0001

BV=bevacizumab, Cape=capecitabine, Tax/Anthra=taxane/anthracycline.* 15 mg/kg cohort.

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Patient Characteristics, Pooled Population

Non-BV(n1008)

BV(n1439)

Age, median 55 yr 56 yr

Triple-negative disease, % 26 25

Disease-free interval (≤24 mo), % 39 37

Prior adjuvant chemo, % 64 62

Taxane 22 24

Anthracycline 52 48

Visceral disease, % 71 69

≥3 metastatic sites, % 38 41

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Progression-Free Survival, Pooled Population

Non-BV(n=1008)

BV(n=1439)

Median, mo 6.7 9.2

HR (95% CI) 0.64 (0.57–0.71)

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Analysis of PFS by Subgroups

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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

30

Overall Survival, Pooled Population

Non-BV(n=1008)

BV(n=1439)

Median, mo 26.4 26.7

HR (95% CI) 0.97 (0.86–1.08)

1-yr survival rate (%)

77 82

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Use of Subsequent Systemic Therapies in AVADO and RIBBON-1 Studies*

%Non-BV(n654)

BV(n1071)

Any chemotherapy 71 65

Bevacizumab 51 40

Any hormonal therapy 25 23

# of subsequent anti-cancer agents

≥4 27 23

3 15 12

2 27 26

1 10 15

*Data not available from E2100.

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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.

A look at TNBC

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Facts and Prejudices

• Regrowth• Toxicity• Age• Cost

D Miles, JCO 2011

From discontinuation to death

V Ranpura, JAMA 2011

Bevacizumab and FAEs

Bevacizumab and FAEs

V Ranpura, JAMA 2011

T Choueiri, JCO 2011

Bevacizumab and CHF

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Safety, Causes of Death*

%Non-BV(n982)

BV(n1679)

Total deaths 55.8 51.3

MBC 51.5 47.4

Treatment-related 1.8 2.1

Other 1.4 1.5

Missing 1.0 0.3

*Safety evaluable patient population.

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Grade ≥3 Selected Adverse Events (AEs), Pooled Population

%Non-BV(n982)

BV(n1679)

Neutropenia

7.1 10.0

Sensory neuropathy

8.5 9.5

Hypertension

1.2 9.0

Febrile neutropenia

3.5 6.5

Venous thromboembolic event

3.8 2.8

Proteinuria

0 2.3

Arterial thromboembolic event

0.3 1.6

Bleeding

0.4 1.5

Left ventricular systolic function

0.2 1.5

Wound dehiscence

0.3 0.8

Fistula

0.3 0.5

GI perforation

0.3 0.5

RPLS

0 <0.1

RPLS=Reversible posterior leukoencephalopathy syndrome.

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Grade ≥3 Selected Adverse Events (AEs), Pooled Population

%Non-BV(n982)

BV(n1679)

Neutropenia

7.1 10.0

Sensory neuropathy

8.5 9.5

Hypertension

1.2 9.0

Febrile neutropenia

3.5 6.5

Venous thromboembolic event

3.8 2.8

Proteinuria

0 2.3

Arterial thromboembolic event

0.3 1.6

Bleeding

0.4 1.5

Left ventricular systolic funct.

0.2 1.5

Wound dehiscence

0.3 0.8

Fistula

0.3 0.5

GI perforation

0.3 0.5

RPLS

0 <0.1

RPLS=Reversible posterior leukoencephalopathy syndrome.

Elderly Patients

X Pivot, EJC 2011

TJ Smith, & BE Hillner, NEJM 2011

Cost-Effectiveness

Conclusions

• 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?

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

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