bevacizumab: antiangiogenic therapy for breast cancer: where do we stand? fortunato ciardiello...

Bevacizumab: Antiangiogenic therapy for breast cancer: where do

we stand?

Fortunato Ciardiello

Division of Medical Oncology,

Department of Clinical and Experimental Medicine,

Second University of Naples, Italy

VEGF

Survival Migration

Proliferation

ANGIOGENESIS

Endothelial cell

Binding andactivation ofVEGF receptor

Release VEGF

H2O2

PDGF

IGF-1TGF

IL-6

bFGF

Hypoxia COX-2

NO Oncogenes

VEGF as a key mediator of angiogenesis

Upstream activators of VEGF synthesis

Downstreamsignaling pathways

Antibodies

Tyrosine kinase inhibitors

Rationale for anti-VEGF therapy in breast cancer

VEGF expression is increased in many tumour types including breast cancer1

Positive correlation between VEGF levels and poor clinical outcome, including patient survival2

• VEGF levels correlate with response to chemo/radiotherapy3

Anti-VEGF treatment inhibits growth of human breast tumour xenografts in animals4

1Brown LF, et al. Hum Pathol 1995;26:86–91 2Linderholm B, et al. J Clin Oncol 2000;18:1423–31 3Gasparini G, et al. Cancer J Sci Am 1999;5:101–11

4Borgstrom P, et al. Anticancer Res 1999;19:4203–14

VEGF = vascular endothelial growth factor

Phase II trials of Bevacizumab plus chemotherapy in MBC

Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer (AVF2324s)

Two-stage design• 19 patients recruited. 6 responses required for a further 18 patients to

be recruited

Primary endpoint: response rate

Secondary endpoints include time to progression and safety

Treatment administration• Bevacizumab 10mg/kg i.v. every 2 weeks• vinorelbine 25mg/m2 i.v. weekly. Dose adjusted following ANC

assessment

Bevacizumab(10mg/kg every

2 weeks) + vinorelbine

PD

ANC = absolute neutrophil count

Refractory breast cancer

Burstein HJ, et al. Breast Cancer Res Treat 2002;79: S115 (Abstract 446)

Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer (AVF2324s): efficacy

Data from 54 evaluable patients

Number of patients (%)

Complete response 1 (2)

Partial response 16 (29)

Stable disease 25 (45)

Progressive disease 12 (21)


Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer (AVF2324s): safety

Data from 55 evaluable patients

Grade (number of patients)

1 2 3 4

Haematologic 10 5 27 15

Non-haematologic Hypertension Pericardial effusion Proteinuria Thrombosis Haemorrhage Epistaxis Vomiting Neurosensory

11 0

11 0 3

10 15 26

3 0 2 1 0 0 3 1

0 1 1 1 0 1 4 1

0 0 0 0 0 0 0 0


Phase II trial of Bevacizumab plus vinorelbine in refractory breast cancer(AVF2324s): conclusions

Bevacizumab plus vinorelbine has clinical activity• 31% of patients had an objective response• several patients had responses of >1 year, which is encouraging

This combination was well tolerated• side effects relating to Bevacizumab included hypertension and

epistaxis

Studies in less heavily pretreated patients may be warranted


Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s):

study design

Primary endpoints: response rate, overall survival and toxicity

Secondary endpoints: correlative studies

• baseline plasma VEGF

• soluble activated endothelial cell markers and adhesion molecules

• microvessel density by CD31 immunohistochemistry

• tumour and endothelial cell apoptosis by TUNEL assay

Bevacizumab(10mg/kg every

2 weeks) + docetaxel X 6

PDMetastatic breast cancer (n=27)

Bevacizumab alone

Docetaxel 35mg/m2 weekly for 3 weeks of a 4-week cycle

Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9

• Metastatic disease measurable by RECIST

• 0–1 prior chemotherapy regimens for metastatic disease

• ECOG PS 0–2

• At least 6 months since prior taxane therapy

• No brain metastases

• No major surgical procedure or significant traumatic injury within 28 days

Phase II trial of Bevacizumab plus weekly docetaxel

in MBC (AVF2326s): eligibility criteria


Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s): efficacy summary

Response n (%)

Complete response 0 (0)

Partial response 14 (52)

Stable disease 9 (33)

Overall response 14 (52)

Withdrawn due to toxicity prior to 2 cycles

2 (7)

Median progression-free survival (months)[95% CI]

7.5[6.2–8.3]

Median duration of response (months)[95% CI]

6.0[4.6–6.5]



in MBC (AVF2326s): Avastin-related toxicity

Bevacizumab plus docetaxel(n=27)

Grade 2 Grade 3 Grade 4

Hypertension, n (%) 4 (14.8) 1 (3.7)

0

Proteinuria, n (%) 11 (40.7) 0 0

Epistaxis, n (%) 1 (3.7) 0 0

Thromboembolic events, n (%)

0 0 2 (7.4)



in MBC (AVF2326s): other toxicities

Bevacizumab plus docetaxel (n=27)

Grade 2 Grade 3 Grade 4

Dyspnoea, n (%) 18 (66.7) 1 (3.7) 0

Eye tearing, n (%) 15 (55.6) 0 0

Fatigue, n (%) 19 (70.3) 4 (14.8) 0

Leukopenia, n (%) 3 (11.1) 6 (22.2) 1 (3.7)

Neutropenia, n (%) 2 (7.4) 4 (14.8) 1 (3.7)

Infection, n (%) 4 (14.8) 0 1 (3.7)

Neuropathy, n (%) 3 (11.1) 2 (7.4) 0

Stomatitis, n (%) 9 (33.3) 2 (7.4) 0


Phase II trial of Bevacizumab plus weekly docetaxel in MBC (AVF2326s):

summary

Efficacy data from this first reported clinical trial of Avastin and docetaxel are encouraging• the response rate of 52% shows that this is an active

combination

Toxicity was acceptable: • the only grade 4 adverse event attributable to Avastin was

venous thromboembolism in two patients

• most toxicity was consistent with the safety profile of weekly docetaxel

This regimen is worthy of further investigation in a randomised phase III trial


A phase II trial is investigating Avastin 15mg/kg plus docetaxel 75mg/m2 every 3 weeks in treatment-naïve MBC

Primary endpoint: time to progression

43 of 75 patients have been enrolled• 21 have had at least one assessment

Response rate is 40%

The most common grade 3/4 adverse events to date are neutropenia, febrile neutropenia and hypertension• LVEF decline seen in one patient

This regimen is well tolerated and appears active in this patient population

Ongoing phase II trial of Bevacizumab plus docetaxel in MBC (AVF3110s)

Chan D, et al. J Clin Oncol 2006;24(20 June suppl.):605s (Abstract 13047)

Phase III trials of Bevacizumab plus chemotherapy in MBC

Phase III trial of Bevacizumab plus Xeloda

® in MBC (AVF2119g)

Primary endpoint: progression-free survival

Secondary endpoints: overall response rate, duration of response and overall survival

Treatment administration

• Bevacizumab 15mg/kg i.v. every 3 weeks

• Xeloda 2,500mg/m2 orally daily for 2 weeks of a 3-week cycle

Previously treated MBC (n=462)

Xeloda(n=230)

Xeloda + Avastin 15mg/kg every 3 weeks (n=232)

PD

PD*

Miller KD, et al. J Clin Oncol 2005;23:792–9*No cross over was permitted

Phase III trial of Bevacizumab and chemotherapy

in relapsed/refractory MBC (AVF2119g)

Inclusion criteria• prior anthracycline and taxane treatment

— one or two prior chemotherapy regimens for MBCor

— relapse within 12 months of completing anthracycline- and taxane-containing adjuvant therapy

• ECOG PS 0 or 1

Exclusion criteria• antitumour therapy within 21 days• anticoagulation therapy• CNS metastases (head CT or MRI required)

Miller KD, et al. J Clin Oncol 2005;23:792–9


Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): patient

characteristics

Xeloda (n=230)

Xeloda + Avastin (n=232)

Median age, years (range) 52 (30–77) 51 (29–78)

Visceral disease (%) 80.0 77.6

ER+ (%) 51.7 41.8

HER2+ (%) 20.4 26.3

Treatment setting First-line (%) Second-line (%) Third-line + (%)

16.1 42.6 41.3

15.1 46.1 38.8

Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): progression-free

survival

*Determined by independent review facility where available

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

1.0

0.8

0.6

0.4

0.2

0

Progression-free survival (months)*

Pro

port

ion p

rogre

ssio

n-f

ree

4.17 4.86

Xeloda alone (n=230)(median progression-free survival = 4.17 months)

Xeloda + Bevacizumab (n=232)(median progression-free survival = 4.86 months)

HR=0.98; p=0.857


Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): duration of survival

Pro

port

ion

su

rviv

ing

Duration of survival (months)

1.0

0.8

0.6

0.4

0.2

0

Xeloda alone (n=230)

(median survival = 14.5 months)

Xeloda + Bevacizumab (n=232)

(median survival = 15.1 months)

0 1 2 3 4 5 6 7 8 9 10111213141516 17 18 19


Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): efficacy summary

Xeloda alone

(n=230)

Xeloda + Avastin (n=232) p-value

Overall response rate (%) Inv IRF

19.1 9.1

30.2 19.8

0.006 0.001

Progression-free survival (months)

4.17

4.86

0.857

Overall survival (months) 14.5 15.1 –


Inv = determined by investigatorsIRF = determined by independent review facility

Phase III MBC trial of Bevacizumab and chemotherapy (AVF2119g): grade 3/4 adverse

events

*No grade 4

Incidence (%)

Adverse event

Xeloda (n=215)

Xeloda + Avastin (n=229)

Hypertension* 0.5 17.9

Proteinuria* 0 0.9

Thrombosis 3.7 5.6

Hand-foot syndrome* 24.2 27.5

Bleeding* 0.5 0.4

CHF/cardiomyopathy 1 3

Nausea* 1.9 2.6


Phase III trial of Bevacizumab in first-line MBC (E2100)

This trial focuses on a less heavily pretreated population than AVF2119g

Primary endpoint: progression-free survival (PFS)

Other endpoints: overall response rate, overall survival, quality of life, correlative studies

Previously untreated MBC

(n=722)

Paclitaxel (n=354)

Paclitaxel + Bevacizumab

10mg/kg every2 weeks (n=368)

PD*

PD

*No cross over will be permittedMiller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)

Phase III trial of Bevacizumab in first-line MBC (E2100): eligibility

criteria

Locally recurrent or MBC

• HER2+ only if prior treatment with Herceptin (trastuzumab) or contraindication

No prior chemotherapy regimens for MBC

• adjuvant taxane allowed if disease-free interval >12 months

ECOG PS 0 or 1

No antitumour therapy within 21 days

No CNS metastases (head CT or MRI required)

No significant proteinuria (>500mg/24 hours)

No therapeutic anticoagulation

HER = human epidermal growth factor receptor CT = computed tomographyMRI = magnetic resonance imaging

Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)

Phase III trial of Bevacizumab in first-line MBC (E2100): patient characteristics

56 (29-84)

42

43

65

18

59

5

55 (27-85)

42

43

64

18

64

4

Median age, range (years)

Disease-free interval

<24 months (%)

>3 sites (%)

Adjuvant chemotherapy (%)

Taxane (%)

ER+ (%)

HER2+ (%)

Paclitaxel + Bevacizumab(n=341)

Paclitaxel (n=339)

Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)ER = oestrogen receptor

0.0

0.2

0.4

0.6

0.8

1.0

Months

Pro

gre

ssio

n-f

ree s

urv

ival pro

port

ion

0 6 12 18 24 30

Phase III trial of Bevacizumab in first-line

MBC (E2100): progression-free survival

HR = 0.51 (0.43-0.62)

Log rank test p<0.0001

Bevacizumab + paclitaxel: 11.4 monthsPaclitaxel: 6.11 months

484 events reported (89% of required events)


HR = hazard ratio

6.11 11.4


MBC (E2100): progression-free survival

Group Ratio 95% CI

ER+, PR+ER+, PR-ER–, PR–

No adj chemoNon-taxane Taxane

Age 27–49Age 50–64Age 65–85

DFI 0–24 monthsDFI >24 months

<3 sites≥3 sites

Overall

0.390.860.47

0.600.510.38

0.450.440.79

0.570.47

0.480.54

0.51

(0.29, 0.53)(0.52, 1.43)(0.35, 0.63)

(0.44, 0.82)(0.39, 0.67)(0.25, 0.59)

(0.32, 0.63)(0.33, 0.58)(0.53, 1.17)

(0.43, 0.75)(0.37, 0.60)

(0.37, 0.61)(0.41, 0.71)

(0.43, 0.62)

0.0 0.5 1.0 1.5Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)


MBC (E2100): overall response rateO

vera

ll re

sponse

rate

(%

)

339 341 262 236

p<0.0001

p<0.0001

Paclitaxel

Bevacizumab + paclitaxel

13.8

29.9

16.0

37.7


0

10

20

30

40

All patients Measurable disease

0.0

0.2

0.4

0.6

0.8

1.0

Months

Overa

ll su

rviv

al

pro

port

ion

0 6 12 18 24 30 36

Phase III trial of Bevacizumab in first-line MBC (E2100): overall survival

Bevacizumab + paclitaxel: 28.4 months Paclitaxel: 25.2 months

HR = 0.84 (0.64, 1.05)

Log rank test: p=0.12

275 events reported (57% of required events) Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)

Phase III trial of Bevacizumab in first-line MBC

(E2100): NCI-CTC grade 3 and 4 toxicities

NCI-CTC v3.0, worst per patient NCI-CTC = National Cancer Institute common toxicity criteria

Paclitaxel(n=332)

Paclitaxel + Bevacizumab

(n=350)

Grade 3 Grade 4 Grade 3 Grade 4

Hypertension* (%)

2 0 15 <1

Thromboembolic events (%)

2 2 2 0

Bleeding† (%) 0 0 2 <1

Proteinuria§ (%) 0 0 1 1

*p<0.0001; †p=0.02; §p=0.002


Phase III trial of first-line Bevacizumab in MBC (E2100): summary

Addition of Bevacizumab to paclitaxel significantly increased progression-free survival, the primary endpoint of the trial

Addition of Bevacizumab to paclitaxel significantly increased overall response rate in all patients and in patients with measurable disease

Overall survival data are preliminary, after only 57% of required events

The combination of Bevacizumab and paclitaxel was well tolerated, with no unexpected side effects reported


Ongoing and future trials of Bevacizumab in MBC

Planned phase III trial of Bevacizumab plus docetaxel in MBC (AVADO): study

design

Randomised, double-blind, placebo-controlled, multicentre, phase III trial


Secondary endpoints: overall response rate, duration of response, time to treatment failure, overall survival, safety, quality of life

Recruitment commenced March 2006


(n=705)

Docetaxel +

placeboPD

Docetaxel + Bevacizumab

7.5mg/kg every3 weeks

Docetaxel + Bevacizumab

15mg/kg every3 weeks

Docetaxel – 100mg/m2 every three weeks

PD

PD

AVADO: key eligibility criteria

Chemonaïve locally recurrent or metastatic breast cancer

Aged ≥18 years, female

ECOG performance status 0–1

HER2-negative; documented oestrogen/progesterone receptor status

Prior adjuvant chemotherapy permitted if relapse ≥6 months since last dose (≥12 months if taxane based)

No uncontrolled hypertension

Ongoing trials of Bevacizumab in breast cancer: RIBBON 1 (AVF3694g)


Chemotherapy regimen is determined by investigator prior to randomisation

Trial already open in USA and will be opening in other countries during 2006*Continuation or cross over to Avastin after confirmation of PD is allowed at the

discretion of the investigator

Taxane-based or anthracycline-based or

Xeloda + Avastin 15mg/kg

every 3 weeks

Taxane-based or anthracycline-based or

Xeloda + placebo


(n=950)

PD*

PD*

Randomise 2:1

2

1

Planned trial of docetaxel and Herceptin with or without Bevacizumab

(AVEREL)

Primary endpoint: progression-free survivalSecondary endpoints: response rate, duration of response, overall survival, safetyStart date: Q3 2006

Previously untreated HER2+

MBC (n=320)

Docetaxel + Herceptin

Docetaxel + Herceptin + Avastin 15mg/kg

every 3 weeksPD

PD*

* No cross-over permitted

Bevacizumab in MBC: summary

Bevacizumab monotherapy has activity in patients with MBC

Bevacizumab plus paclitaxel significantly prolongs progression-free survival, and significantly improves response rate

Ongoing trials are evaluating Bevacizumab with other chemotherapy agents and in other settings, including the adjuvant and neoadjuvant settings

bevacizumab: antiangiogenic therapy for breast cancer: where do we stand? fortunato ciardiello...

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