Charla GGCP/GECP 2-2012

1. Bevacizumab!
Martín Lázaro!
CHUVI!

2. Ann Surg 1972;175:409-16
Angiogenic
Switch
1-2 mm
VEGF
Small tumor Larger tumor
• Nonvascular • Vascular
• Dormant • Metastatic potential

3. Ann Surg 1972;175:409-16
Angiogenic
Switch
1-2 mm
VEGF
Small tumor Larger tumor
• Nonvascular • Vascular
• Dormant • Metastatic potential

5. ''If you have cancer and you
are a mouse, we can take
good care of you''!

6.
Trial
N
Schema
Results
Johnson et al! 99! Carboplatin/paclitaxel! PFS: 7.4 m (15 arm)!
phase II; random! Carbo/paclitaxel/beva 15/7.5! PFS: 4.2 m!
JCO 2004!
Nishio et al! 180! Cisplatin/gemcitabine! PFS : 5.4 m!
phase II; random! Cisplatine/gemcit/beva 15! PFS: 6.6 m!
ASCO 2009!

7.
Trial
N
Schema
Results
Johnson et al! 99! Carboplatin/paclitaxel! PFS: 7.4 m (15 arm)!
phase II; random! Carbo/paclitaxel/beva 15/7.5! PFS: 4.2 m!
JCO 2004!
Nishio et al! 180! Cisplatin/gemcitabine! PFS : 5.4 m!
phase II; random! Cisplatine/gemcit/beva 15! PFS: 6.6 m!
ASCO 2009!
ECOG 4599! 878! Carboplatin/paclitaxel! PFS: 4.5 m!
phase III; ! OS: 10.3 m!
randomized! ! !
NEJM 2006! Carbo/paclitaxel/beva 15 mg/kg! PFS: 6.2 m!
OS: 12.3 m!
AVAiL! 1043! Cisplatin/gemcitabine! PFS: 6 m!
phase III, ! OS: 13 m!
randomized! ! !
JCO 2009! Cisplatin/gemc/bevacizumab 7.5! PFS: 6.7 m!
! OS: 13.6 m!
! !
Cisplatin/gemc/bevacizumab 15! PFS: 6.5 m !
OS: 13.4 m!

8. E4599: Efficacy
RR: 15% for Carboplatin (CbP) vs 35% for CbP + Bevacizumab
PFS OS
100
CbP
100
CbP
CbP
+
bevacizumab
CbP
+
bevacizumab
80
80
P < .001; HR: 0.66 P = .003; HR: 0.79
Median PFS: 6.2 mos vs Median OS: 12.3 mos vs
Patients Surviving (%)
60
4.5 mos 60
10.3 mos
Patients
With
PFS
(%)
6-mos PFS: 55% vs 33% 1-yr OS: 51% vs 44%
40
1-yr PFS: 15% vs 6% 2-yr OS: 23% vs 15%
40
20
20
0
0
0
6
12
18
24
30
36
0
6
12
18
24
30
36
Mos
Mos
Sandler A, et al. N Engl J Med. 2006;355:2542-2550.
.

9. 13 m
6.5 m

10. Lima ABC, PLoS ONE 2011;6(8):e22681.
Fav
CT-­‐bev
Botrel et al; Lung Cancer (2011) doi:10:1016/j.lungcan.2011.01.028

11. Adverse
events
of
special
interest
Grade
1
Grade
2
Grade
3
Grade
4
Grade
5
Grade
>
3
Number
of
Resolved
Improved
Persistent
Led
to
events
death
Bleeding
32
%
6
%
3
%
<1
%
1
%
4
%
Bleeding
Epistaxis
1347
24
%
3
%
86
%
1
%
3
%
<1
%
10
%
0
1
%
1
%
Pulm
haemorrhage
7
%
1
%
<1
%
<1
%
<1
%
1
%
Hypertension
CNS
bleeding
<1
%
1025
0
76
%
<1
%
9
%
0
15
%
%
<1
<1
%
0
Hypertension
16
%
14
%
5
%
<1
%
0
6
%
Proteinuria
1046
70
%
10
%
20
%
0
Proteinuria
21
%
10
%
3
%
<1
%
0
3
%
Thromboembolism
324
48
%
18
%
26
%
8
%
Thromboembolism
2
%
4
%
5
%
2
%
1
%
8
%
Gastrointestinal
30
60
%
10
%
3
%
27
%
perforation
Gastrointestinal
<1
%
<1
%
1
%
<1
%
<1
%
1
%
perforation
Wound-­‐healing
31
71
%
6
%
23
%
0
complications
Wound-­‐healing
1
%
<1
%
<1
%
<1
%
0
<1
%
complications
Congestive
heart
18
33
%
11
%
22
%
33
%
failure
Congestive
heart
<1
%
<1
%
<1
%
<1
%
<1
%
<1
%
failure
Crino et al; Lancet Oncol 2010; 11:733-40

12. Adverse
events
of
special
interest
Number
of
Resolved
Improved
Persistent
Led
to
events
death
Bleeding
1347
86
%
3
%
10
%
1
%
Hypertension
1025
76
%
9
%
15
%
0
Proteinuria
1046
70
%
10
%
20
%
0
Thromboembolism
324
48
%
18
%
26
%
8
%
Gastrointestinal
30
60
%
10
%
3
%
27
%
perforation
Wound-­‐healing
31
71
%
6
%
23
%
0
complications
Congestive
heart
18
33
%
11
%
22
%
33
%
failure
Crino et al; Lancet Oncol 2010; 11:733-40

13. E4599: Efficacy in Elderly Subgroup
Efficacy Outcome Elderly (≥ 70 Yrs of Age) Nonelderly (< 70 Yrs of Age)
Paclitaxel/ Paclitaxel/ Paclitaxel/ Paclitaxel/
Carboplatin + Carboplatin Carboplatin + Carboplatin
Bevacizumab (n = 113) Bevacizumab (n = 320)
(n = 111) (n = 306)
Median OS, m 11.3 12.1 12.8 9.6
1-yr OS, % 46 50 53 42
Median PFS, m 5.9 4.9 6.2 4.4
T-R mortality 6.3 % 2.6 %
Ramalingam SS, et al. J Clin Oncol. 2008;26:60-65.
Brain Metastases on Bevacizumab
Clinical Trial Patients With CNS Events
Brain Metastases
PASSPORT (phase II)1 n = 115 with treated No CNS
1st/2nd-line chemo+ bev N = 115 brain mts hemorrhage
ARIES (observational cohort study)2 n = 101 with brain 1 CNS
Bevacizumab in 1st-line N = 1518 metastases hemorrhage
1. Fischbach NA, et al. 2009 ASCO. Abstract 8040.
2. Crino L, et al. Lancet Oncol. 2010;11:733-740.

14. BIOMARKERS
VEGF plasma levels
VEGF SNPs
ICAM-1
Citokines/chemokines
Hypertension: ECOG
1.0
P
=
NS
Medians
0.8
HTN:
14.0
mos
No
HTN:
11.3
mos
0.6
0.4
0.2
0
0
10
20
30
40
50
60
70

15. BIOMARKERS RESISTANCE
VEGF plasma levels EGFR, FGFR, HGF/
MET associated with
VEGF SNPs
VEGF inhibitor
ICAM-1
resistance
Citokines/chemokines
Hypertension: ECOG Targeting resistance
1.0
P
=
NS
Medians
pathways may reduce
0.8
HTN:
14.0
mos
No
HTN:
11.3
mos
0.6
the onset of resistance
0.4
0.2
0
0
10
20
30
40
50
60
70

16. BIOMARKERS RESISTANCE COMBINED
VEGF plasma levels EGFR, FGFR, HGF/ + erlotinib:
MET associated with BeTa
VEGF SNPs
VEGF inhibitor ATLAS
ICAM-1
resistance
+ cetuximab
Citokines/chemokines
S0536
Hypertension: ECOG Targeting resistance
1.0
P
=
NS
S0819
Medians
pathways may reduce
HTN:
14.0
mos
0.8
No
HTN:
11.3
mos
+ pemetrexed
0.6
the onset of resistance
0.4
AVAPERL
0.2
Pointbreak
0
0
10
20
30
40
50
60
70

17. BEVACIZUMAB
Summary

18. BEVACIZUMAB CT + Bev combination
Summary increase the RR and PFS
Benefits on overall survival
are modest

19. BEVACIZUMAB CT + Bev combination
Summary increase the RR and PFS
Benefits on overall survival
are modest
Hemoptysis remains an issue
Anticoagulation: caution
Safe in patients with treated
brain metastases

20. BEVACIZUMAB CT + Bev combination
Summary increase the RR and PFS
Benefits on overall survival
are modest
Hemoptysis remains an issue
Younger women have greater
Anticoagulation: caution
benefit from bevacizumab
Safe in patients with treated
than older women
brain metastases
Caution with elderly patients