Transcript Avastin® (bevacizumab) in metastatic breast cancer (MBC)

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 as a key mediator of angiogenesis
TGFa
IL-6
bFGF
Antibodies
Hypoxia 
COX-2 
NO 
Oncogenes

IGF-1
Upstream activators
of VEGF synthesis
PDGF
H2O2
Release VEGF
Binding and
activation of
VEGF receptor
VEGF
Endothelial cell
Tyrosine kinase
inhibitors
Survival
Migration
Proliferation
ANGIOGENESIS
Downstream
signaling pathways
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
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
2Linderholm
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)
Refractory breast
cancer
Bevacizumab
(10mg/kg every
2 weeks) +
vinorelbine
PD
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
ANC = absolute neutrophil
count
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
Number of patients (%)
Complete response
1 (2)
Partial response
16 (29)
Stable disease
25 (45)
Progressive disease
12 (21)
Data from 54 evaluable patients
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
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
Data from 55 evaluable patients
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
Metastatic breast
cancer (n=27)
Bevacizumab
(10mg/kg every
2 weeks) +
docetaxel X 6
Bevacizumab
alone
PD
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
Docetaxel 35mg/m2 weekly for 3 weeks of a 4-week cycle
Ramaswamy B, et al. Clin Cancer Res 2006;12:3124–9
Phase II trial of Bevacizumab plus weekly docetaxel
in MBC (AVF2326s): eligibility criteria
• 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
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
Hypertension, n (%)
Proteinuria, n (%)
Epistaxis, n (%)
Thromboembolic events, n (%)
4 (14.8)
Grade 3
Grade 4
1 (3.7)
0
11 (40.7)
0
0
1 (3.7)
0
0
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
Ongoing phase II trial of Bevacizumab plus
docetaxel in MBC (AVF3110s)
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
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)
Xeloda
(n=230)
PD*
Previously treated
MBC (n=462)
Xeloda + Avastin 15mg/kg
every 3 weeks (n=232)
PD
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
*No cross over was permitted
Miller KD, et al. J Clin Oncol 2005;23:792–9
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 MBC
or
— relapse within 12 months of completing anthracycline- and taxanecontaining 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)
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
Median age, years (range)
Miller KD, et al. J Clin Oncol 2005;23:792–9
Phase III MBC trial of Bevacizumab and
chemotherapy (AVF2119g): progression-free survival
Proportion progression-free
1.0
0.8
Xeloda alone (n=230)
(median progression-free survival =
4.17 months)
0.6
Xeloda + Bevacizumab (n=232)
(median progression-free survival =
4.86 months)
HR=0.98; p=0.857
0.4
0.2
0
4.17
0
1
2
3
4.86
4 5 6 7 8 9 10 11 12 13 14 15 16
Progression-free survival (months)*
*Determined by independent review facility where available
Miller KD, et al. J Clin Oncol 2005;23:792–9
Proportion surviving
Phase III MBC trial of Bevacizumab and
chemotherapy (AVF2119g): duration of survival
1.0
Xeloda alone (n=230)
(median survival = 14.5 months)
0.8
Xeloda + Bevacizumab (n=232)
(median survival = 15.1 months)
0.6
0.4
0.2
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Duration of survival (months)
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)
Overall response rate (%)
Inv
IRF
Progression-free survival
(months)
Overall survival (months)
19.1
9.1
4.17
14.5
Xeloda +
Avastin
(n=232)
30.2
19.8
4.86
15.1
p-value
0.006
0.001
0.857
–
Inv = determined by investigators
IRF = determined by independent review facility
Miller KD, et al. J Clin Oncol 2005;23:792–9
Phase III MBC trial of Bevacizumab and chemotherapy
(AVF2119g): grade 3/4 adverse events
Incidence (%)
Adverse event
Xeloda
(n=215)
Xeloda + Avastin
(n=229)
Hypertension*
0.5
17.9
Proteinuria*
0
0.9
Thrombosis
3.7
5.6
24.2
27.5
Bleeding*
0.5
0.4
CHF/cardiomyopathy
1
3
Nausea*
1.9
2.6
Hand-foot syndrome*
*No grade 4
Miller KD, et al. J Clin Oncol 2005;23:792–9
Phase III trial of Bevacizumab
in first-line MBC (E2100)
Previously
untreated MBC
(n=722)
Paclitaxel (n=354)
PD*
Paclitaxel +
Bevacizumab
10mg/kg every
2 weeks (n=368)
PD
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
*No cross over will be permitted
Miller 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 tomography
MRI = 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
55 (27-85)
Paclitaxel +
Bevacizumab
(n=341)
56 (29-84)
<24 months (%)
42
42
>3 sites (%)
43
43
Adjuvant chemotherapy (%)
64
65
Taxane (%)
18
18
ER+ (%)
64
59
HER2+ (%)
4
5
Paclitaxel
(n=339)
Median age, range (years)
Disease-free interval
ER = oestrogen receptor
Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)
Phase III trial of Bevacizumab in first-line
MBC (E2100): progression-free survival
Bevacizumab + paclitaxel: 11.4 months
Paclitaxel: 6.11 months
Progression-free survival proportion
1.0
0.8
HR = 0.51 (0.43-0.62)
0.6
Log rank test p<0.0001
0.4
0.2
6.11
0.0
0
HR = hazard ratio
484 events reported (89% of
required events)
11.4
6
12
Months
18
24
30
Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)
Phase III trial of Bevacizumab in first-line
MBC (E2100): progression-free survival
Group
Ratio 95% CI
ER+, PR+
ER+, PRER–, PR–
0.39
0.86
0.47
(0.29, 0.53)
(0.52, 1.43)
(0.35, 0.63)
No adj chemo
Non-taxane
Taxane
0.60
0.51
0.38
(0.44, 0.82)
(0.39, 0.67)
(0.25, 0.59)
Age 27–49
Age 50–64
Age 65–85
0.45
0.44
0.79
(0.32, 0.63)
(0.33, 0.58)
(0.53, 1.17)
DFI 0–24 months
DFI >24 months
0.57
0.47
(0.43, 0.75)
(0.37, 0.60)
<3 sites
≥3 sites
0.48
0.54
(0.37, 0.61)
(0.41, 0.71)
Overall
0.51
(0.43, 0.62)
Miller KD, et al. Breast Cancer Res Treat
2005;94:S6(Abstract 3)
0.0
0.5
1.0
1.5
Phase III trial of Bevacizumab in first-line
MBC (E2100): overall response rate
Paclitaxel
p<0.0001
Bevacizumab + paclitaxel
p<0.0001
Overall response rate (%)
40
29.9
30
20
37.7
16.0
13.8
10
339
341
262
236
0
All patients
Measurable disease
Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)
Phase III trial of Bevacizumab in
first-line MBC (E2100): overall survival
Bevacizumab + paclitaxel: 28.4 months
Overall survival proportion
1.0
Paclitaxel: 25.2 months
0.8
0.6
0.4
HR = 0.84 (0.64, 1.05)
Log rank test: p=0.12
0.2
0.0
0
6
275 events reported (57% of required
events)
12
18
24
30
36
Months
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
Paclitaxel +
Bevacizumab
(n=350)
Paclitaxel
(n=332)
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
NCI-CTC v3.0, worst per patient
*p<0.0001; †p=0.02; §p=0.002
NCI-CTC = National Cancer Institute common toxicity criteria
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
Docetaxel
+
placebo
PD
Previously
untreated MBC
(n=705)
Docetaxel + Bevacizumab
7.5mg/kg every
3 weeks
PD
Docetaxel – 100mg/m2 every
three weeks
Docetaxel + Bevacizumab
15mg/kg every
3 weeks
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 commenced March 2006
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)
Randomise 2:1
2
Previously
untreated MBC
(n=950)
1
Taxane-based or
anthracycline-based or
Xeloda
+ Avastin 15mg/kg every 3
weeks
PD*
Taxane-based or
anthracycline-based or
Xeloda
+ placebo
PD*
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
Planned trial of docetaxel and Herceptin
with or without Bevacizumab (AVEREL)
Docetaxel + Herceptin
PD*
Docetaxel + Herceptin
+ Avastin 15mg/kg every
3 weeks
PD
Previously untreated
HER2+ MBC
(n=320)
Primary endpoint: progression-free survival
Secondary endpoints: response rate, duration of response,
overall survival, safety
Start date: Q3 2006
* 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