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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)
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): 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
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): 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
Burstein HJ, et al. Breast Cancer Res Treat 2002;79: S115 (Abstract 446)
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
Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9
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]
Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9
Phase II trial of Bevacizumab plus weekly docetaxel
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)
Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9
Phase II trial of Bevacizumab plus weekly docetaxel
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
Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9
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
Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9
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
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
Miller KD, et al. J Clin Oncol 2005;23:792–9
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
Miller KD, et al. J Clin Oncol 2005;23:792–9
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 –
Miller KD, et al. J Clin Oncol 2005;23:792–9
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
Miller KD, et al. J Clin Oncol 2005;23:792–9
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)
Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)
HR = hazard ratio
6.11 11.4
Phase III trial of Bevacizumab in first-line
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)
Phase III trial of Bevacizumab in first-line
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
Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)
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
Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)
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
Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)
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
Primary endpoint: progression-free survival
Secondary endpoints: overall response rate, duration of response, time to treatment failure, overall survival, safety, quality of life
Recruitment commenced March 2006
Previously untreated MBC
(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)
Primary endpoint: progression-free survival
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
Previously untreated MBC
(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