Bevacizumab: Antiangiogenic therapy for breast cancer: where do we stand

1
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
2
VEGF as a key mediator of angiogenesis
TGFa
IL-6
IGF-1
Upstream activators of VEGF synthesis
bFGF
PDGF
H2O2
Hypoxia ?COX-2 ?NO ?Oncogenes ?
Release VEGF
Binding andactivation ofVEGF receptor
Antibodies
Endothelial cell
Tyrosine kinase inhibitors
Downstream signaling pathways
Survival
Migration
Proliferation
ANGIOGENESIS
3
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 1995268691
2Linderholm B, et al. J Clin Oncol
200018142331 3Gasparini G, et al. Cancer J
Sci Am 1999510111 4Borgstrom P, et al.
Anticancer Res 199919420314
VEGF vascular endothelial growth factor
4
Phase II trials of Bevacizumab plus chemotherapy
in MBC
5
Phase II trial of Bevacizumab plus vinorelbine
in refractory breast cancer (AVF2324s)
Bevacizumab (10mg/kg every 2 weeks) vinorelbine
Refractory breast cancer
PD

• Two-stage design
• 19 patients recruited. ³6 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
200279 S115 (Abstract 446)
6
Phase II trial of Bevacizumab plus vinorelbine in
refractory breast cancer (AVF2324s) efficacy
Data from 54 evaluable patients
Burstein HJ, et al. Breast Cancer Res Treat
200279 S115 (Abstract 446)
7
Phase II trial of Bevacizumab plus vinorelbine in
refractory breast cancer (AVF2324s) safety
Data from 55 evaluable patients
Burstein HJ, et al. Breast Cancer Res Treat
200279 S115 (Abstract 446)
8
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 gt1 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
200279 S115 (Abstract 446)
9
Phase II trial of Bevacizumab plus weekly
docetaxel in MBC (AVF2326s) study design
Bevacizumab (10mg/kg every 2 weeks) docetaxel
X 6
Metastatic breast cancer (n27)
PD
Bevacizumab alone

• 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 20061231249
10
Phase II trial of Bevacizumab plus weekly
docetaxel in MBC (AVF2326s) eligibility criteria

• Metastatic disease measurable by RECIST
• 01 prior chemotherapy regimens for metastatic
  disease
• ECOG PS 02
• 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 20061231249
11
Phase II trial of Bevacizumab plus weekly
docetaxel in MBC (AVF2326s) efficacy summary
Ramaswamy B, et al. Clin Cancer Res 20061231249
12
Phase II trial of Bevacizumab plus weekly
docetaxel in MBC (AVF2326s) Avastin-related
toxicity
Ramaswamy B, et al. Clin Cancer Res 20061231249
13
Phase II trial of Bevacizumab plus weekly
docetaxel in MBC (AVF2326s) other toxicities
Ramaswamy B, et al. Clin Cancer Res 20061231249
14
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 20061231249
15
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 200624(20 June
suppl.)605s (Abstract 13047)
16
Phase III trials of Bevacizumab plus chemotherapy
in MBC
17
Phase III trial of Bevacizumab plus Xeloda in
MBC (AVF2119g)
Xeloda (n230)
PD
Previously treated MBC (n462)
Xeloda Avastin 15mg/kg every 3 weeks (n232)
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

Miller KD, et al. J Clin Oncol 2005237929
No cross over was permitted
18
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 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 2005237929
19
Phase III MBC trial of Bevacizumab and
chemotherapy (AVF2119g) patient characteristics
Miller KD, et al. J Clin Oncol 2005237929
20
Phase III MBC trial of Bevacizumab and
chemotherapy (AVF2119g) progression-free survival
1.0 0.8 0.6 0.4 0.2 0
Xeloda alone (n230) (median progression-free
survival 4.17 months) Xeloda Bevacizumab
(n232) (median progression-free survival 4.86
months) HR0.98 p0.857
Proportion progression-free
4.17
4.86
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Progression-free survival (months)
Miller KD, et al. J Clin Oncol 2005237929
Determined by independent review facility where
available
21
Phase III MBC trial of Bevacizumab and
chemotherapy (AVF2119g) duration of survival
Xeloda alone (n230) (median survival 14.5
months) Xeloda Bevacizumab (n232) (median
survival 15.1 months)
1.0 0.8 0.6 0.4 0.2 0
Proportion surviving
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 2005237929
22
Phase III MBC trial of Bevacizumab and
chemotherapy (AVF2119g) efficacy summary
Inv determined by investigators IRF
determined by independent review facility
Miller KD, et al. J Clin Oncol 2005237929
23
Phase III MBC trial of Bevacizumab and
chemotherapy (AVF2119g) grade 3/4 adverse events
No grade 4
Miller KD, et al. J Clin Oncol 2005237929
24
Phase III trial of Bevacizumab in first-line MBC
(E2100)
Paclitaxel (n354)
PD
Previously untreated MBC (n722)
Paclitaxel Bevacizumab 10mg/kg every2 weeks
(n368)
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
200594S6(Abstract 3)
25
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
  gt12 months
• ECOG PS 0 or 1
• No antitumour therapy within 21 days
• No CNS metastases (head CT or MRI required)
• No significant proteinuria (gt500mg/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
200594S6(Abstract 3)
26
Phase III trial of Bevacizumab in first-line MBC
(E2100) patient characteristics
Paclitaxel Bevacizumab (n341)
Paclitaxel (n339)
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
lt24 months () gt3 sites () Adjuvant
chemotherapy () Taxane () ER () HER2 ()
ER oestrogen receptor
Miller KD, et al. Breast Cancer Res Treat
200594S6(Abstract 3)
27
Phase III trial of Bevacizumab in first-line MBC
(E2100) progression-free survival
Bevacizumab paclitaxel 11.4 months
1.0
Paclitaxel 6.11 months
0.8
HR 0.51 (0.43-0.62) Log rank test plt0.0001
0.6
Progression-free survival proportion
0.4
0.2
6.11
11.4
0.0
0
6
12
18
24
30
Months
HR hazard ratio
484 events reported (89 of required events)
Miller KD, et al. Breast Cancer Res Treat
200594S6(Abstract 3)
28
Phase III trial of Bevacizumab in first-line MBC
(E2100) progression-free survival
Group
Ratio
95 CI
ER, PR
0.39
(0.29, 0.53)
ER, PR-
0.86
(0.52, 1.43)
ER, PR
0.47
(0.35, 0.63)
No adj chemo
0.60
(0.44, 0.82)
Non-taxane
0.51
(0.39, 0.67)
Taxane
0.38
(0.25, 0.59)
Age 2749
0.45
(0.32, 0.63)
Age 5064
0.44
(0.33, 0.58)
Age 6585
0.79
(0.53, 1.17)
DFI 024 months
0.57
(0.43, 0.75)
DFI gt24 months
0.47
(0.37, 0.60)
lt3 sites
0.48
(0.37, 0.61)
3 sites
0.54
(0.41, 0.71)
Overall
0.51
(0.43, 0.62)
Miller KD, et al. Breast Cancer Res Treat
200594S6(Abstract 3)
29
Phase III trial of Bevacizumab in first-line MBC
(E2100) overall response rate
Paclitaxel Bevacizumab paclitaxel
plt0.0001
plt0.0001
40
37.7
29.9
30
Overall response rate ()
20
16.0
13.8
10
339
341
262
236
0
All patients
Measurable disease
Miller KD, et al. Breast Cancer Res Treat
200594S6(Abstract 3)
30
Phase III trial of Bevacizumab in first-line MBC
(E2100) overall survival
Bevacizumab paclitaxel 28.4 months
1.0
Paclitaxel 25.2 months
0.8
0.6
Overall survival proportion
HR 0.84 (0.64, 1.05) Log rank test p0.12
0.4
0.2
0.0
0
6
12
18
24
30
36
Months
275 events reported (57 of required events)
Miller KD, et al. Breast Cancer Res Treat
200594S6(Abstract 3)
31
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
plt0.0001 p0.02 p0.002
Miller KD, et al. Breast Cancer Res Treat
200594S6(Abstract 3)
32
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
200594S6(Abstract 3)
33
Ongoing and future trials of Bevacizumab in MBC
34
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

35
AVADO key eligibility criteria

• Chemonaïve locally recurrent or metastatic breast
  cancer
• Aged 18 years, female
• ECOG performance status 01
• 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

36
Ongoing trials of Bevacizumab in breast cancer
RIBBON 1 (AVF3694g)
Randomise 21
Taxane-based or anthracycline-based or Xeloda
Avastin 15mg/kg every 3 weeks
2
PD
Previously untreated MBC (n950)
1
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
37
Planned trial of docetaxel and Herceptin with or
without Bevacizumab (AVEREL)
Docetaxel Herceptin
PD
Previously untreated HER2 MBC (n320)
Docetaxel Herceptin Avastin 15mg/kg every 3
weeks
PD

• Primary endpoint progression-free survival
• Secondary endpoints response rate, duration of
  response, overall survival, safety
• Start date Q3 2006

No cross-over permitted
38
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