david miles chair at the mount vernon cancer centre, middlesex, uk
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David Miles Chair at the Mount Vernon Cancer Centre, Middlesex, UK. Past Senior Lecturer and Consultant in Medical Oncology at Guy’s and St Thomas’ Hospital, London - PowerPoint PPT PresentationTRANSCRIPT
David MilesChair at the Mount Vernon Cancer Centre,
Middlesex, UK Past Senior Lecturer and Consultant
in Medical Oncology at Guy’s and St Thomas’ Hospital, London
Received awards from the British Association of Cancer Research, the American Society of Clinical Oncology and the American Association for Cancer Research
Published numerous papers on breast cancer and biological therapies
On Institutional Review Board for Cancer Research UK and UK National Institute for Clinical Excellence committee for the treatment of early stage breast cancer
Mount Vernon Hospital
Innovation + strength = effective management for HER2-negative
metastatic breast cancer
David MilesMount Vernon Hospital
Middlesex, UK
Introduction
Breast cancer is the leading cause of cancer mortality in women worldwide
Improvements in detection and therapy of early breast cancer have greatly improved survival– many patients still go on to develop recurrent or
metastatic disease
Aims of therapy for systemic disease– slow/halt disease progression– extend survival– maintain patient QoL through symptom relief
QoL = quality of life
Potentially hormone responsive
CYTOTOXIC CHEMOTHERAPY WITH OR WITHOUT TRASTUZUMAB
Postmenopausal
Ov Abl Tamoxifen Tamoxifen
AI
on progression
Metastatic breast cancer (MBC)Aggressive visceral disease
Other metastatic patterns
Premenopausal
No response Ov Abl AI
No responseor on
progression
Ov Abl = ovarian ablation; AI = aromatase inhibitor
VinorelbineVarious
Changing options in MBC (1980s)
Anthracyclines
Taxanes Capecitabine
SERMS(tamoxifen)
AIs(letrozole)
SERDS(faslodex)
First line Second lineThird line
SERMS = selective oestrogen-receptor modulatorsSERDS = selective oestrogen-receptor down regulators
VinorelbineVarious
Changing options in MBC (1990s)
Anthracyclines
Taxanes Capecitabine
SERMS(tamoxifen)
AIs(letrozole)
SERDS(faslodex)
First lineSecond line
± trastuzumab
VinorelbineVarious
Changing options in MBC (2000s)
Anthracyclines
Taxanes Capecitabine
SERMS(tamoxifen)
AIs(letrozole)
SERDS(faslodex)
First line
± trastuzumab
Treatment scenario 1
You are treating a patient with the following characteristics
– 62-year-old woman
– HER2-negative, hormone receptor-negative MBC
• metastasis to bone
– no prior chemotherapy for metastatic disease
– adjuvant therapy with both doxorubicin and paclitaxel2 and a half years previously
• did not tolerate taxane well (neuropathy)
What treatment would you recommend?
Capecitabine
Intestine
Liver
Capecitabine
CE
5'-DFCR
CyD
5'-DFUR
Tumour
5'-DFCR
CyD
5'-DFUR
5-FU
Thymidinephosphorylase (TP)
5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine;CyD = cytidine deaminase; CE = carboxyl esterase; 5-FU = 5-fluorouracil
Enzymatic activation of capecitabine
More 5-FU in the tumour with TP-activated capecitabine
Schüller J, et al. Cancer Chemother Pharmacol 2000;45:291–7
Normal tissue
*Ratio of median values
5-FU
5-FU
5-FU
5-FU
Tumour tissue
5-FU
5-FU 5-FU5-FU
5-FU
5-FU
5-FU5-FU
5-FU
Plasma
x 3.2* x 21.4*
Capecitabine monotherapy has activity in first-line MBC (phase II trials)
TrialC dose (mg/m2,
twice daily)RR (%)
Median TTP (months)
Median OS (months)
O’Shaughnessy et al.1 C1,250
(n=61) 30 4.1 19.6
Soto et al.2 C1,250
(n=91) 46 8.4*,† 24+*
Bajetta et al.3
C1,250
(n=30) 37 3.9 10
C1,000
(n=43) 35 4.1 16
1O’Shaughnessy J, et al. Ann Oncol 2001;12:1247–542Soto C, et al. J Clin Oncol 2006;24(Suppl. 18):20s (Abstract 570)
3Bajetta E, et al. J Clin Oncol 2005;23:2155–61
*Includes patients receiving a taxane following capecitabine monotherapy; †PFS
C = capecitabine; RR = response rate;TTP = time to progression; OS = overall survival;PFS = progression-free survival
Key phase III trial of first-linecapecitabine monotherapy versus oral CMF
Primary endpoints: PFS (efficacy), quality-adjusted PFS (effectiveness)
Secondary endpoints: RR, health-related QoL, OS and safety
MBC patients unsuitable for
intensive chemotherapy
Stratified for institution, PS, liver or brain metastases,
planned use of bisphosphonates/
prednisone
Continuous capecitabine650mg/m2 b.i.d., days 1–21, every 3 weeks
Intermittent capecitabine1,000mg/m2 b.i.d., days 1–14, every 3 weeks
Classical CMFOral cyclophosphamide 100mg/m2 days 1–14i.v. methotrexate 40mg/m2 days 1, 8 i.v. 5-FU 600mg/m2 day 1, 8, every 4 weeks
RANDO MISATION
b.i.d. = twice daily; i.v. = intravenous; CMF = cyclophosphamide, methotrexate and 5-FU; PS = performance status
Stockler MR, et al. J Clin Oncol 200725(Suppl. 18):39s (Abstract 1031)
Capecitabine versus CMF baseline characteristics: a relatively young, fit
population
%Int C
(n=107)Cont C (n=107)
CMF (n=109)
Age <60 60
3664
4753
4456
ECOG 0–1 88 88 86
Liver/brain metastases 45 48 47
Diagnosis advanced disease 4y 56 52 56
ER+ or PR+ 62 67 64
Adjuvant chemotherapy CMF AC+CMF AC Taxane
1910 6 2
20 9 5 4
21 7 5 4
Prior endocrine therapy 78 82 79
Stockler MR, et al. J Clin Oncol 200725(Suppl. 18):39s (Abstract 1031)
Int = intermittent; Cont = continuousECOG = Eastern Cooperative Oncology Group
Capecitabine versus CMF: similarresponse rates
%Int C
(n=107)Cont C (n=107)
CMF (n=109)
Overall RR Complete (CR) Partial (PR)
22 418
20 020
18 117
Stable disease (SD) 39 46 41
Disease control rate (CR+PR+SD) 61 66 59
Patients receiving therapy for 12 months 19 17 5
Stockler MR, et al. J Clin Oncol 2007;25(Suppl. 18):39s (Abstract 1031)
Capecitabine versus CMF: significantsurvival benefit with capecitabine
Median (months)
Capecitabine (intermittent)+ continuous 22
CMF 18
0 6 12 18 24 30 36 42 48Months
1.0
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n a
live
HR = hazard ratio; CI = confidence interval
Log-rank p=0.02HR=0.72 (95% CI: 0.55–0.94)
Stockler MR, et al. J Clin Oncol 2007;25(Suppl. 18):39s (Abstract 1031)
Capecitabine monotherapy is well tolerated
Intermittent capecitabine
Continuous capecitabine
CMF
*
*
**
†
*p≤0.0001 X versus CMF;†p=0.03 X versus CMF
Gra
de
3/4
adve
rse
even
ts (
%)
Stockler MR, et al. J Clin Oncol 2007;25(Suppl. 18):39s (Abstract 1031)
50
40
30
20
10
0
Hand-fo
ot
syndro
me
Neutro
penia
Febril
e
neutro
penia
Stom
atiti
s
Infe
ctio
n
Alopec
ia
Other
toxi
citie
s
Capecitabine monotherapy has proven efficacy across all lines of therapy
ORR (%)
Median TTP (months)
Median OS (months)
Anthracycline and taxane naïve1–3 22–37 3.9–4.1 10.0–24.0
Anthracycline pretreated4,5 36–46 3.0 7.6
Anthracycline and taxanepretreated6–11 15–28 3.0–5.0 10.1–15.9
1Stockler MR, et al. J Clin Oncol 2007;25(Suppl. 18):39s (Abstract 1031) 2Bajetta E, et al. J Clin Oncol 2005;23:2155–61
3O’Shaughnessy J, et al. Ann Oncol 2001;12:1247–54; 4Talbot D, et al. Br J Cancer 2002;86:1367–725Soto C, et al. J Clin Oncol 2006;24(Suppl. 18):20s (Abstract 570)
6Blum J, et al. J Clin Oncol 1999;17:485–937Largillier R, et al. Ann Oncol 2006;17(S9) (Abstract 161P); 8Miller K, et al. J Clin Oncol 2005;23:792–9
9Mavroudis D, et al. J Clin Oncol 2006;24(Suppl. 18):42s (Abstract 658) 10Reichardt P, et al. Ann Oncol 2003;14:1227–33; 11Blum J, et al. Cancer 2001;92:1759–68
ORR = overall response rate
Capecitabine plus docetaxel first line significantly extends TTP: pivotal clinical trial
4.2 6.1
CD (n=255)
Docetaxel (n=256)
Log-rank p=0.0001; HR=0.652
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Est
imat
ed p
rob
abil
ity
Months
O’Shaughnessy J, et al. J Clin Oncol 2002;20:2812–23
1.0
0.8
0.6
0.4
0.2
0
CD = capecitabine + docetaxel
Capecitabine plus docetaxel first line significantly extends OS: pivotal clinical trial
Miles D, et al. Clin Breast Cancer 2004;5:273–8Minimum follow-up = 27 months
11.5 14.5
CD Docetaxel
Log-rank p<0.01; HR=0.777
0 4 8 12 16 20 24 28 32 36 40 44 48
Est
imat
ed p
rob
abil
ity
Months
1.0
0.8
0.6
0.4
0.2
0
CD: most common (>5%) grade 3/4 treatment-related toxicities
Stom
atiti
s
50
40
30
20
10
0
Pat
ien
ts (
%)
Diarrh
oea
Hand-fo
ot
syndro
me
Nause
a
Fatig
ue/
asth
enia
Neutro
penic
feve
r
CD (n=251)
Docetaxel (n=255)
Grade 3Grade 4
Grade 3Grade 4
O’Shaughnessy J, et al. J Clin Oncol 2002;20:2812–23
Failure, or resistance to an anthracycline-based
therapy given in the neoadjuvant, first or
second-line metastatic setting
and
two non-adjuvant regimens of
chemotherapy
Phase III trial of capecitabine with docetaxelin anthracycline-resistant MBC (NO16853)
RANDO MISATION
Primary endpoint: equivalency in TTP or death
Planned sample size: 440 patients
Capecitabineb.i.d. 950mg/m2 day 1–14 every 3 weeks
Docetaxel75mg/m2 (60 minute) i.v.day 1 every 3 weeks
Capecitabineb.i.d. 1,250mg/m2 days 1–14 every 3 weeks
Docetaxel75mg/m2 (60 minute) i.v. day 1 every 3 weeks
Treatment scenario 2
You are treating a patient with the following characteristics– HER2-negative, hormone receptor-negative MBC– no prior chemotherapy for metastatic disease– relatively young (45 years), with good PS– adjuvant therapy with anthracyclines, 3–4
years previously
What treatment would you recommend?
Angiogenesis is essentialfor tumour growth
Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25
Stages at which angiogenesis plays a role in tumour progression
Premalignanttumour
Malignanttumour
Tumourgrowth
Vascularinvasion
Micro-metastases
Metastaticgrowth
Angiogenicswitch
Bevacizumab binds VEGF,the key mediator of angiogenesis
Recombinant humanised monoclonal anti-VEGF antibody
– humanised murine antibody(93% human, 7% murine)
• prevents possible immune reactions
– recognises and binds to all major isoforms of human VEGF-A
• prevents VEGF from interacting with its receptors
• results in the inhibition of activation of downstream signalling pathways
– terminal half-life = 17–21 days
• enables convenient combination with concomitant therapy schedules
Bevacizumab
– P– P
P– P–
VEGF
X
Growth
Proliferation
Migration
Survival
X
VEGF = vascular endothelial growth factor
Phase III trial of bevacizumab plus capecitabine in pretreated MBC (AVF2119g)
Primary endpoint: PFS– secondary endpoints: ORR and OS
*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
Previously treated MBC* (n=462)
Capecitabine (n=230)
Capecitabine + bevacizumab 15mg/kg every 3 weeks (n=232)
Treat to disease progression
Treat to disease progression†
†No cross over was permitted
Capecitabine1,250mg/m2 orally b.i.d. for2 weeks of a 3-week cycle
Miller KD, et al. J Clin Oncol 2005;23:792–9
AVF2119g: patient characteristics
Key baseline patient characteristicsCapecitabine
(n=230)
Bevacizumab + capecitabine
(n=232)
Prior chemotherapy exposure in the metastatic setting (%) 83.9 84.9
One chemotherapy regimen (%) 42.6 46.1
Two or more chemotherapy regimens (%) 41.3 38.8
Prior trastuzumab (%) 23.9 25.0
Prior myeloablative therapy (%) 10.0 9.1
≥3 metastatic sites (%) 50.4 49.1
Visceral disease (%) 80.0 77.6
Miller KD, et al. J Clin Oncol 2005;23:792–9
AVF2119g: efficacy summary
The addition of bevacizumab to capecitabine more than doubled the response rate according to an independent review facility
Capecitabine(n=230)
Bevacizumab + capecitabine (n=232) p value
Overall response rate (%)
Investigators
Independent review facility
19.1
9.1
30.2
19.8
0.006
0.001
Median PFS (months) 4.2 4.9 NS
Median OS (months) 14.5 15.1 NS
NS = not significant Miller KD, et al. J Clin Oncol 2005;23:792–9
AVF2119g: grade 3/4 adverse events
*No grade 4
Adverse eventCapecitabine
(n=215)Bevacizumab +
capecitabine (n=229)
Hypertension* 0.5 17.9
Proteinuria* 0.0 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
CHF = congestive heart failure Miller KD, et al. J Clin Oncol 2005;23:792–9
Angiogenesis: redundancy in the system
Adapted from Folkman J. In: DeVita VT, et al. editors. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005. p. 2865–82
Bevacizumab may be more effective earlier in thecourse of MBC
VEGFVEGFbFGFTGF-1
VEGFbFGFTGF-1PlGF
VEGFbFGFTGF-1PlGFPD-ECGF
VEGFbFGFTGF-1PlGFPD-ECGFPleiotrophin
Breast cancer
Tumour growth
E2100: phase III trial of first-line paclitaxel ± bevacizumab in MBC
Primary endpoint: PFS
Other endpoints: ORR, OS, QoL
Miller KD, et al. N Engl J Med 2007;357:2666–76
Previously untreated locally recurrent or
MBC(n=722)
Paclitaxel(n=354)
Paclitaxel + bevacizumab
10mg/kg every 2 weeks(n=368)
Treat to disease progression*
Treat to disease progression
*No cross over permitted
Paclitaxel:90mg/m2 every week for 3 weeks of a 4-week cycle
*No cross over permitted
E2100: statistical design
Primary endpoint: PFS– 85% power for a 33% improvement
• 6 vs 8 months
Final analysis after 546 PFS– interim analyses after 270 and 425 events
Safety analyses– grade 4 haemorrhage or hypertension
(1% acceptable)– grade 3/4 thrombosis or embolism (5% acceptable)
Miller KD, et al. N Engl J Med 2007;357:2666–76
E2100: treatment arms were well balanced for major prognostic factors
Paclitaxel (n=354)
Bevacizumab + paclitaxel (n=368)
Median age, years (range) 55 (27–85) 56 (29–84)
ER-positive, n (%) 223 (63.0) 223 (60.6)
PR-positive, n (%) 158 (44.6) 166 (45.1)
HER2-positive, n (%) 5 (1.4) 2 (0.5)
Disease-free interval, n (%) 24 months>24 months
146 (41.2)208 (58.8)
150 (40.8)
218 (59.2)
Number of metastatic sites, n (%)<33
252 (71.2) 102 (28.8)
262 (71.2)
106 (28.8)
Prior taxane therapy, n (%) 68 (19.2) 74 (20.1)
Prior anthracycline therapy, n (%) 180 (50.8) 184 (50.0)
ER-positive = oestrogen receptor-positive; PR-positive = progesterone receptor-positive Data on file submitted to CHMP November 07
Bevacizumab plus paclitaxel (E2100): PFS benefitconfirmed by Independent Review Facility (IRF)
11.4
0 6 12 18 24 30 36
PF
S e
stim
ate
5.8 11.3
5.8
Months
1.0
0.8
0.6
0.4
0.2
0
*Scans available for 90% of patients
n PFS by HR
Paclitaxel 354 Investigator0.42
Bevacizumab + paclitaxel 368 Investigator
Data on file submitted to CHMP November 07
Paclitaxel 354 IRF*0.48
Bevacizumab + paclitaxel 368 IRF*
Bevacizumab plus paclitaxel (E2100):consistent PFS benefit in subgroup analysis
Increase inmedian PFS (%)
103
114
126
113
98
55
116
73
Prior adjuvant hormonetherapy (n=343)
Prior adjuvantchemotherapy (n=475)Prior adjuvant taxane
therapy (n=142)Prior adjuvant anthracycline
therapy (n=364)Prior metastatic hormone
therapy (n=262)
ER-positive status (n=446)
24-month disease-freeinterval (n=296)
3 metastatic sites(n=208)
9 monthsMedian PFS*
Months0 5 10 15
*PFS as assessed by IRF
Paclitaxel Bevacizumab + paclitaxel
6.1
5.8
5.8
6.0
6.0
7.7
4.9
4.8
12.4
12.4
13.1
12.8
11.9
11.9
10.6
8.3
Data on file submitted to CHMP November 07
Bes
t re
spo
nse
(%
)
E2100: objective response(patients with measurable disease)
Investigator assessment
(n=525)
IRF assessment(n=472)
50
2223
48
Paclitaxel
Bevacizumab
+ paclitaxel
CR + PRp<0.0001
CR + PRp<0.0001
Data on file submitted to CHMP November 07
60
50
40
30
20
10
0
E2100: increased survival with bevacizumab was seen over the first 30 months
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42 48 54 60
*Post-hoc
p=0.017*
74.0%
81.4%
50.1%
55.0%
p=0.191*
Log-rank p=0.1374; HR=0.869 (95% CI: 0.722–1.046)
Median OS n (months)
Bevacizumab + paclitaxel 368 26.5
Paclitaxel 354 24.8
OS
est
imat
e
MonthsData on file submitted to CHMP November 07
80% power to detect OS 24–31 months
10–15% power to detect OS of 3 months
E2100: increased survival with bevacizumab was seen over the first 30 months
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42 48 54 60
OS
est
imat
e
Months
Median OS n months
Bevacizumab + paclitaxel 368 26.5
Paclitaxel 354 24.8
Data on file submitted to CHMP November 07
E2100: most frequent grade 3adverse events (5% incidence)
#Includes NCI AdEERS mandatory collection in the bevacizumab + paclitaxel arm only, which does not allow valid comparison between the two arms
Data on file submitted to CHMP November 07 NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events
NCI-CTCAE term
Paclitaxel (n = 348)
(%)
Paclitaxel + bevacizumab#
n = 363, (%)
Difference
(%)
Patients with 1 event 50.6 71.1 20.5
Neuropathy 17.5 24.2 6.7
Hypertension 1.4 16.0 14.6
Fatigue 5.2 10.7 5.5
Infection without neutropenia
4.6
9.1
4.5
Neutropenia (grade 4) 3.2 5.8 2.6
Vomiting 2.3 5.5 3.2
Less frequently reportedbevacizumab-related adverse events
CHF/cardiomyopathy– observed in 2.2% of patients treated with bevacizumab plus paclitaxel– caution should be exercised with patients experiencing clinically significant
cardiac disease
ATE and VTE– observed in 3.6% and 3.0% of patients treated with bevacizumab plus paclitaxel– discontinue bevacizumab in patients with symptomatic pulmonary embolism
and those who develop ATE
Wound-healing complications– severe wound-healing complications were observed in 1.1% of patients treated
with bevacizumab plus paclitaxel– bevacizumab should not be initiated for ≥28 days following major surgery or in
patients with unhealed wounds, and should be withheld for elective surgery
GI perforations– observed in <1% of patients treated with bevacizumab plus paclitaxel – permanently discontinue bevacizumab in patients experiencing GI perforation
Data on file submitted to CHMP November 07; Avastin Summary of Product Characteristics (SmPC)
E2100: quality of lifeM
ean
ch
ang
e fr
om
bas
eli
ne
Worse
BetterTOI-B
p=0.0006 (primary analysis)
Baseline Week 17 Week 33
73
–1–5–9
–13–17–21–25–29–33–37–41
p=0.0001
Mea
n c
han
ge
fro
m b
ase
lin
e
Worse
BetterTOT-B
p<0.0001
p=0.0001
Baseline Week 17 Week 33
Bevacizumab+ paclitaxelPaclitaxel
Roche data on file submitted to regulatory authority in 2006
73
–1–5–9
–13–17–21–25–29–33–37–41
TOI-B (Trial Outcome Index) incorporates measures of physical, functional and breast cancer-specific quality of life
TOT-B (Total Score) includes emotional and social/family well-being in addition to the above
E2100: summary
Substantial prolongation of PFS– living without the disease advancing and improving
disease-related symptoms– delaying subsequent lines of therapy and
associated side effects
Higher QoL
Superior 1-year survival
Positive risk:benefit ratio
Bevacizumab plus docetaxel in first-line MBC (AVADO): phase III study design
Recruitment completed in March 2007
– target recruitment was exceeded and 736 patients have been enrolled
Primary endpoint: PFS
– secondary endpoints: ORR, OS, safety, QoL
Data to be presented at ASCO 2008
Previously untreated HER2-negative locally recurrent or
MBC (n=705)
Docetaxel 100mg/m2 every 3 weeks + placebo
Treat todisease
progression
Docetaxel + bevacizumab7.5mg/kg every
3 weeks
Docetaxel + bevacizumab15mg/kg every
3 weeks
PI: David Miles
Treat todisease
progression
Treat todisease
progression
Phase III trial of bevacizumab plus chemotherapy in first-line MBC (RIBBON 1)
Recruitment completed August 2007
Primary endpoint: PFS– secondary endpoints: chemotherapy-specific PFS, objective
response rate, OS, safety
*Continuation or cross over to bevacizumab is allowed at the discretion of the investigator
1
2
Randomisation
PI: Joyce O’Shaughnessy
Anthracycline-based or taxane or capecitabine + bevacizumab 15mg/kg
every 3 weeks
Anthracycline-based or taxane or
capecitabine + placebo
Treat to disease progression*
Previously untreated
MBC (n=1,239)
Treat to disease progression*
Safety study of bevacizumab plus chemotherapy in first-line MBC (MO19391)
Recruitment started Q3 2006– planned in 510 centres from 38 countries worldwide
Primary endpoint: safety– secondary endpoints: time to disease progression, OS, safety
in patients with CNS metastases
Previously untreated HER2-negative locally
recurrent or MBC(n~2,300)
Bevacizumab (10mg/kg every 2 weeks or
15mg/kg every 3 weeks)+
taxane-based chemotherapy*
Treat to disease
progression
PI: Ian Smith
*Taxane use according to routine practice or, if taxanes contraindicated, alternative chemotherapy allowed at physician’s discretionCNS = central nervous system
Smith IE, et al. Eur J Cancer Suppl2007;5:221 (Abstract 2123)
Rationale for combining bevacizumab with hormonal therapy
Evidence suggests that oestrogen directly modulates angiogenesis– regulatory regions of the VEGF gene contain elements
responsive to oestrogen1
– oestrogen upregulates VEGF expression in a breast cancer cell line2
– aromatase inhibitors decrease VEGF levels in a rat model3
The combination of bevacizumab and fulvestrant produced considerably greater growth suppression of breast cancer xenografts than either agent alone4
1Hyder SM, et al. Cancer Res 2000;60:3183–90; 2Takei H, et al. Breast Cancer 2002;9:39–423Nakamura J, et al. Endocrinology 1996;137:5589–96
4Pietras RJ, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S37 (Abstract 507)
Trials of bevacizumab combined with hormonal therapies in MBC
GEICAM 2006-11: phase III study of bevacizumab + letrozole
ER+/PR+ previously untreated locally recurrent or MBC
(n~360)
Aromatase inhibitor or tamoxifen +
bevacizumab 15mg/kg q3w
Aromatase inhibitor or tamoxifen + placebo
Treat to disease progression
Treat to disease progression
CALGB 40503: phase III trial of bevacizumab + endocrine agents
Primary endpoint: progression-free survival, response assessment every9 weeks
Postmenopausal women with advanced or MBC suitable for
endocrine therapy
Letrozole
Letrozole + bevacizumab15mg/kg q3w
Treat to disease progression
Treat to disease progression
Primary endpoint: progression-free survival
Summary
Bevacizumab and capecitabine play integral roles in the treatment algorithm for HER2-negative MBC
Bevacizumab plus paclitaxel is effective and well tolerated and is suitable for most patients with MBC
Single-agent capecitabine has demonstrated efficacy across all lines of MBC therapy
Data from ongoing studies will further expand the use of these agents in MBC