anti-angiogenic therapy: a new approach to the treatment of metastatic breast cancer

Anti-angiogenic therapy:a new approach to the treatment

of metastatic breast cancer

Kathy MillerIndiana University School of Medicine,

USA

VEGF is a central mediator of angiogenesis, the formation of new

blood vessels

Adapted from Carmeliet P. Nat Med 2003;9:653–60SMC = smooth muscle cell

Vasculogenesis

Hemangioblast

Endothelial progenitors

ArteryVEGF

Maturevasculature

SMC

SMC progenitor

Angiogenesis

VEGF

Vein

Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25

Angiogenesis is involved throughout tumor formation, growth and

metastasis

Stages at which angiogenesis plays a role in tumor progression

Premalignantstage

Malignanttumor

Tumorgrowth

Vascularinvasion

Dormantmicrometastasis

Overtmetastasis

(Avasculartumor)

(Angiogenicswitch)

(Vascularisedtumor)

(Tumor cellintravasation)

(Seeding indistant organs)

(Secondaryangiogenesis)

VEGF: a candidate for anticancer therapy

Tumors rely on their existing vasculature for survival• VEGF is a powerful survival factor for the immature vessels that

comprise tumor microvasculature1

The abnormal structure and function of tumor vasculature inhibits the action of conventional therapies2

• inhibition of VEGF normalizes existing vasculature3

Tumors require new vasculature for growth and metastasis4

• VEGF is a potent stimulator of new vessel growth

VEGF has a limited role in healthy adults,5 so anti-VEGF therapy should have minimal physiological effects

1Alon T, et al. Nat Med 1995;1:1024–8 2Netti PA, et al. Proc Natl Acad Sci USA 1999;96:3137–42

3Dvorak HF, et al. Am J Pathol 1995;146:1029–39

4Folkman J, N Engl J Med 1971;285:1182–6; 5Ferrara N, et al. Nat Med 2003;9:669–76

Effects of VEGF inhibition:regression of microvasculature

Inai T, et al. Am J Pathol 2004;165:35–52

Reduction in tumor blood flow after 1 day of anti-VEGF therapy• reduction in vessel patency and blood flow in RIP-Tag2 tumor

vessels treated for 1 day with anti-VEGF therapy (B) and a vehicle control (A), as shown by lectin screening

• over 7 days, this was followed by endothelial cell regression

Effects of VEGF inhibition:modification of existing vasculature

Abnormal vasculature is ‘normalized’ following VEGF inhibition

Inai T, et al. Am J Pathol 2004;165:35–52

Effects of VEGF inhibition:inhibition of new vascular

development

Days after implantation1 6 9

Before implantation

Control

Anti-VEGFtherapy

Osusky KL, et al. Angiogenesis 2004;7:225–33

Neovascularization in a ‘vascular window’ mouse model following implantation of tumor cells and induction of ischaemia

RhuMAb VEGF (bevacizumab)

Recombinant humanized monoclonal anti-VEGF antibody developed from murine anti-VEGF MAb A4.6.11

• 93% human, 7% murine• recognises all major isoforms of

human VEGF, Kd = 8 x 10–10M. Affinity similar to that of the murine antibody

• RhuMAb VEGF binding is restricted to human, non-human primate and rabbit VEGF

• terminal half-life 17–21 days

1Presta LG, et al. Cancer Res 1997;57:4593–9Rhu = recombinant human

Bevacizumab mechanism of action: summary

Bevacizumab may act against tumors in three ways• regression of existing microvasculature• normalization of mature vasculature • inhibition of production of new vasculature

EARLY BENEFIT CONTINUED BENEFIT

Regressionof existing microvasculature

Normalizationof surviving microvasculature

Inhibitionof vessel regrowth and neovascularisation

Phase I/II dose-escalation trial of bevacizumab in MBC: study design

Primary endpoint: overall response rateBevacizumab administered i.v. every 2 weeks until PD or maximum of 13 treatmentsResponse assessment on days 70 and 154• patients with stable disease or better were eligible for extension study

Dosing cohorts

Bevacizumab 3mg/kg every

2 weeks (n=18)

PD


2 weeks (n=41)

PD


2 weeks (n=16)

PD

Previously treated

MBC (n=75)

Cobleigh MA, et al. Semin Oncol 2003;30(5 Suppl. 16):117–24PD = progression of diseasei.v. = intravenous

Phase I/II trial of bevacizumab monotherapy in MBC: efficacy

Bevacizumab (all doses)(n=75)

Overall response rate (%) 9.3

Complete response (%)Partial response (%)

1.38.0

Median duration of response (months)

5.5

Median time to progression (months)

2.4

Median survival (months) 10.2

Cobleigh MA, et al. Semin Oncol 2003;30(5 Suppl. 16):117–24

The efficacy data for this trial compare favorably with those for other agents as monotherapy in similar patient populations

Phase I/II trial of bevacizumab monotherapy in MBC: summary

Headache with nausea and vomiting occurred in 4 patients at 20mg/kg and was dose limiting

Otherwise bevacizumab was well tolerated, with the now typical events associated with this agent • hypertension (23% of patients)

• minor bleeding (epistaxis, 25.3%)

• venous thromboembolism (4%)

• proteinuria (24%)

A bevacizumab dose of 10mg/kg every 2 weeks produced the best therapeutic ratio in this population of heavily pretreated patients

Cobleigh MA, et al. Semin Oncol 2003;30(5 Suppl. 16):117–24

Phase I/II clinical trials of bevacizumab in breast cancer:

summary

Bevacizumab has been combined with several other therapeutic agents in phase I/II trials in locally advanced/recurrent or MBC

• vinorelbine1

• docetaxel2

• erlotinib3

• trastuzumab4

• letrozole5

Efficacy and safety data from these trials suggest that these combinations are worthy of further investigation 1Burstein HJ, et al. Breast Cancer Res Treat 2002;76:Abstract 446

2Ramaswamy B, et al. Breast Cancer Res Treat 2003;81:Abstract 2243Dickler M, et al. J Clin Oncol 2004;22(15 July Suppl.):Abstract 2001

4Pegram M, et al. Breast Cancer Res Treat 2004;88:Abstract 30395Traina TA, et al. Breast Cancer Res Treat 2005 94: Abstract 2030

Phase III trial of bevacizumab plus capecitabine in MBC

(AVF2119g)

Primary endpoint: progression-free survival

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

Treatment administration• bevacizumab 15mg/kg i.v. every 3 weeks• capecitabine 2,500mg/m2 orally daily for 2 weeks of a 3-week cycle

Previously treated MBC (n=462)

Capecitabine(n=230)

Capecitabine + bevacizumab 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 MBC trial of bevacizumab and capecitabine: efficacy summary

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

Capecitabine alone

Bevacizumab +

capecitabine

p-value

Overall response rate (%)

Inv 19.1 30.2 0.006

IRF 9.1 19.8 0.001

Progression-free survival (months)

4.17 4.86 0.857

Overall survival (months)

14.5 15.1 –

Inv = investigatorIRF = independent review facility

Phase III MBC trial of bevacizumab and capecitabine: grade 3/4 adverse

events

*No grade 4

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

Adverse eventCapecitabine

(n=215)

Bevacizumab + capecitabine

(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 (%)

1.0 3.0

Nausea (%)* 1.9 2.6

Breast cancer

VEGF VEGFbFGFTGF-1

VEGFbFGFTGF-1PlGF

VEGFbFGFTGF-1PlGFPD-ECGFPleiotrophin

VEGFbFGFTGF-1PlGFPD-ECGF

Adapted from Relf M, et al. Cancer Res 1997;57:963–9

tumor growth

bFGF = basic fibroblast growth factorTGF-1 = transforming growth factor beta-1PlGF = placental growth factorPD-ECGF = platelet-derived endothelial cell growth factor

Progression of angiogenic activity in human tumors

Phase III MBC trial of bevacizumab and capecitabine: summary

The combination of bevacizumab and capecitabine was well tolerated, with no increase in capecitabine-related toxicities

Addition of bevacizumab to capecitabine produced a significant increase in response rate, but did not result in longer progression-free survival, the primary trial endpoint

As a tumor progresses, the angiogenic pathways involved become more numerous and redundant; the optimal timing for use of bevacizumab is likely to be at an earlier stage

RANDOMIZE

Paclitaxel + bevacizumab

Paclitaxel

28-day cycle:Paclitaxel 90 mg/m2 days 1, 8 and 15Bevacizumab 10 mg/kg days 1 and 15

Phase III trial of first-line bevacizumab

in MBC (E2100): study design

Stratify:• disease-free interval (DFI) ≤24 months vs >24 months• <3 vs ≥3 metastatic sites• adjuvant chemotherapy yes vs no• estrogen receptor (ER)-positive vs -negative vs status

unknown

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


in MBC (E2100): key eligibility criteria

Locally recurrent or metastatic breast cancer• HER2+ only if prior treatment with trastuzumab

No prior chemotherapy regimens for MBC• Adjuvant taxane allowed if DFI >12 months

ECOG PS 0 or 1

No antitumor therapy within 21 days

No CNS metastases (head CT or MR required)

No significant proteinuria (>500 mg/24 hr)

No therapeutic anticoagulationMiller KD, et al. Breast Cancer Res Treat 2005;94:S6 (Abstract 3)


in MBC (E2100): statistical design

Primary endpoint: progression-free survival (PFS)• 85% power for a 33% improvement

— 6 vs 8 months

• One-sided type I error ≈ 2.5% required 650 eligible patients

Final analysis after 546 PFS events• Interim analyses after 270 and 425 events• Asymmetric boundaries to stop early either for

demonstrated benefit or for lack of benefit

Safety analyses• Grade 4 hemorrhage or hypertension (1% acceptable)• Grade 3/4 thrombosis or embolism (5% acceptable)



in MBC (E2100): current analysis

Study activated December 21, 2001

Closed March 24, 2004

680 eligible patients• Most common reasons for ineligibility:

Baseline evaluation >4 weeks from entry (11) Hormonal therapy within 3 weeks (10)

Data cut-off September 27, 2005

484 events• Progression – 426• Death without documented progression – 58



in MBC (E2100): patient characteristics

Paclitaxel (n=339)

Pac + bev (n=341)

Median age 55 (27–85) 56 (29–84)

DFI ≤24 months 42% 42%

≥3 sites 43% 43%

Adjuvant chemotherapy 64% 65%

Taxane 18% 18%

ER+ 64% 59%

HER2+ 4% 5%



in MBC (E2100): response

Paclitaxel Pac + bev

339

29.9%

13.8%

p<0.0001

All patients

40

30

20

10

0

Overa

ll re

sponse

rate

341

16%

37.7%

Measurable disease

236262

p<0.0001


Months

PFS

pro

bab

ility


in MBC (E2100): progression-free survival

HR = 0.51 (0.43–0.62)

Log rank test p<0.0001

Pac + bev 11.4 months

Paclitaxel 6.11 months

484 events reported

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30



in 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)

Su

rviv

al p

rob

ab

ility


in MBC (E2100): overall survival

HR = 0.84 (0.64–1.05)

Log rank test p=0.12

275 events reported

Months

1.0

0.8

0.6

0.4

0.2

0.00 6 12 18 24 30 36

Pac + bev 28.4 months Paclitaxel 25.2 months



in MBC (E2100): bevacizumab toxicity

NCI-CTC v3.0, worst per patient*p<0.0001; **p=0.02; ***p=0.002

Paclitaxel (n=332)

Pac + bev (n=350)

Grade 3 (%)

Grade 4 (%)

Grade 3 (%)

Grade 4 (%)

Hypertension* 2 0 15 <1

Thromboembolic 2 2 2 0

Bleeding** 0 0 2 <1

Proteinuria*** 0 0 1 1


Paclitaxel (n=332)

Pac + bev (n=350)

Grade 3 (%)

Grade 4 (%)

Grade 3 (%)

Grade 4 (%)

Neuropathy 17 1 22 1

Fatigue* 4 <1 8 <1

Neutropenia NR 3 NR 4

LVEF 0 0 <1 0


in MBC (E2100): other grade 3/4 toxicities

↓LVEF = decreased left ventricular ejection fraction

*p=0.05

NCI-CTC v3.0, worst per patient



in MBC (E2100): FACT-B

310 252 198 301 220 167

Mean and 95% CI

Baseline 17 weeks 33 weeks95

100

105

110Pac + bev

Paclitaxel

FAC

T-B

tota

l



in MBC (E2100): FACT-GFA

CT-G

tota

l

75

80

85

311 254 200 303 223 168

Baseline 17 weeks 33 weeks

Mean and 95% CI

Pac + bev

Paclitaxel


Phase III trial of first-line bevacizumab in MBC (E2100): ongoing correlative

studies

Circulating markers• Serum VCAM-1• Urine VEGF

Analysis of primary tumor samples• VEGF expression• VEGF polymorphisms


Phase III trial of first-line bevacizumab in MBC (E2100): conclusions and future

directions

Addition of bevacizumab to paclitaxel• Significantly prolongs progression-free survival• Increases objective response rate• Longer follow-up required to assess impact on overall survival

Further studies should • Explore the role of bevacizumab in the adjuvant setting• Develop methods to identify patients who are most likely to

benefit from VEGF-targeted therapies


E2104 Adjuvant Pilot Trial

REGISTER

Doxorubicin 60 mg/m2 plus Cyclophosphamide 600 mg/m2 Bevacizumab 10 mg/kgevery 14 days x 4

Arm A: ddBAC >BT >B

Arm B: ddAC >BT >B

Doxorubicin 60 mg/m2 plus Cyclophosphamide 600 mg/m2 every 14 days x 4

Paclitaxel 175 mg/m2 Bevacizumab 10 mg/kg every 14 days x 4

Paclitaxel 175 mg/m2 Bevacizumab 10 mg/kg every 14 days x 4

Bevacizumab 10 mg/kg every 14 days x 18

Bevacizumab 10 mg/kg every 14 days x 22

*Hormone therapy and radiation per standard care

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

design

Previously untreated MBC

(n=705)

Docetaxel +

placeboPD

Docetaxel + bevacizumab 7.5mg/kg every

3 weeksDocetaxel +

bevacizumab 15mg/kg every

3 weeks

Docetaxel – 100mg/m2 every three weeks

PD

PD

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

Primary endpoint: progression-free survival

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

Recruitment to commence late March 2006

Conclusions

Bevacizumab is the first anti-angiogenic agent with proven clinical benefit in breast cancer

Bevacizumab is well tolerated in patients with breast cancer, with side effects that are easily managed

Combination of bevacizumab with other agents does not increase the frequency or severity of chemotherapy-related toxicities

Bevacizumab significantly improves progression-free survival and response rate in patients with locally advanced or MBC when used first line in combination with paclitaxel

Acknowledgements

ECOG Operations• Christine Sceppa• Pam Cogliano• Michelle Parent

ECOG Statistical Office• Robert Gray• Molin Wang• Mark Powell

CTEP• Jeff Abrams• Helen Chen

Genentech• Robert Mass• Ginny Langmuir• Amy Sing

IU• Anita Rush-Taylor• Robin Zon• George Sledge

Investigators

Patients

anti-angiogenic therapy: a new approach to the treatment of metastatic breast cancer

Documents

effects of vegf inhibition

antivegf therapy b

monoclonal antivegf

major isoforms of human

tumor formation

j pathol

murine antivegf mab

function of tumor vasculature