RUOLO DELLA TERAPIA ANTIANGIOGENICA NEL CARCINOMA MAMMARIO Rilevanza delle Evidenze Scientifiche

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




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


Hazard Ratios for Disease Progression


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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35

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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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RUOLO DELLA TERAPIA ANTIANGIOGENICA NEL CARCINOMA MAMMARIO Rilevanza delle Evidenze Scientifiche

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