Clinical trials of Avastin bevacizumab in colorectal cancer CRC

1
Highlights in the management of colorectal
cancer Therapeutic antibodies Bevacizumab
Roma, 1-2 February 2007 Vincenzo
Adamo Oncologia Medica e Terapie
Integrate A.O.Universitaria, Policlinico
G.Martino Messina
2
Angiogenesis
is the growth of new blood vessels from existing
vessels and plays an a role in tumor development
Inhibitors Thrombospondin (TSP) Angiostatin Endost
atin Vasostatin Heparin Prolactin Growth
hormone Canstatin Tumstatin Interferon-a (IFN-a)

• Activators
• VEGF
• Acid-FGF
• Basic-FGF
• TGF-a, b
• EGF
• TNF-a
• Angiogenin
• IL-8
• Angiopoietin-1, 2

Ferrara N. Kidney Int 199956794814
3
The Angiogenic Switch is necessary...for Tumor
Growth and Metastasis
Angiogenic switch
Tumor is dormant

• Neovascularization
• Allows rapid tumorgrowth by providingoxygen,
  nutrients, and waste removal
• Facilitates metastasis

Tumor secretion of angiogenic factors stimulates
angiogenesis TAF
Rapid tumor growth and metastasis
Somatic mutation
Smallavascular tumor
Carmeliet and Jain. Nature. 2000 407249
Bergers and Benjamin. Nat Rev Cancer. 2003
3401.
4
Angiogenesis role of VEGF

• Key mediator of angiogenesis
• Stimulates growth of endothelial cells
• Also known as VEGF-A
• Related molecules are VEGF-B, C D, placental
  growth factor (PIGF)
• Homodimeric glycoprotein
• Molecular weight 45,000Da
• Binds VEGF receptor-2 and heparin
• Four molecular species
• VEGF121 VEGF165 VEGF189 VEGF206

Predominant molecular species
Ferrara N, et al. Endocr Rev 199718425
5
Angiogenesis VEGF family, receptors, signal
transduction and its effects
VEGF-A
VEGF-AVEGF-BPlGF
VEGF-C VEGF-D
? Permeability
VEGF receptor-1
VEGF receptor-2
Cation channel
VEGF receptor-3
P
P
P
P
P
P
P
P
P
Ca2
P
PLC
P
P
IP3
PLC
Calcium release
DAG
PLC
DAG
P13K
Protein kinase C
MAPK
SAPK/ JNK
Raf-1
Protein kinase B
Apoptosis Survival
Proliferation Migration
Proliferation, migration ? Permeability
VEGF binding to VEGF receptor-2 activates a
signalling cascade resulting in cellular effects
Shibuya M. Cell Struct Funct 2001262535
6
Anti-VEGF antibody Bevacizumab

• Recombinant humanised monoclonal anti-VEGF
  antibody 93 human, 7 murine
• Recognises all major isoforms of human VEGF
• RhuMAb VEGF binding is restricted to human
• Bevacizumab binds VEGF, preventing interaction
  with its receptors and activation of downstream
  signalling pathways
• This ultimately leads to vascular regression,
  leaving the tumour dormant

X
X
Growth Proliferation Migration Survival
7
Agents targeting the VEGF pathway
???
Antibodies inhibiting VEGF(e.g. bevacizumab)
Antibodies inhibiting VEGF receptors
Soluble VEGF receptors (VEGF-TRAP)
? Permeability
VEGF
Cation channel
VEGF receptor-2
Small-molecules inhibiting VEGF receptors
(TKIs)(e.g. PTK-787)
P
P
P
P
P
P
P
P
P
P
P
P
Migration, permeability, DNA synthesis, survival
Ribozymes (Angiozyme)
Angiogenesis
Lymphangiogenesis
8
Angiogenesis therapeutic rational to inhibition
of VEGF

• Prevent tumor angiogenesis
• ? Inhibition of tumor and metastasis growth
• Reduce tumoral vascularization and normalize
  vascular permeability and tumoral interstitial
  pressure
• ? easier penetration of the tumor by
  chemotherapeutic agents
• Induce vascular regression
• ?possible tumoral dormancy

Jain RK. Nat Med 200179879Willett CG, et al.
Nat Med 2004101457
9
Bevacizumab in clinical development overview
Phase II
Phase III
Phase I
Combined with IFL in previously untreated
mCRC 5mg/kg every 2 weeks (n813) Hurwitz H, et
al. 2004
Combined with either FOLFOX4 or XELOX in
previously untreated mCRC (n1,920)
Dose-escalation trial in solid malignancies.
Safety and pharmacokinetics (n25) Gordon MS, et
al. 2001
AVANT combined with FOLFOX4 or XELOX in stage
II/III colon cancer 5mg/kg every 2 weeks or
7.5mg/kg every 3 weeks (n3,450)
AVAIL combined with CG in previously untreated
stage IIIb, IV or recurrent NSCLC 7.5 or 15mg/kg
every 3 weeks (n830)
Combined with chemotherapy in metastatic
cancers 3mg/kg every week (n12) Margolin K, et
al. 2001
AVOREN combined with IFN-?2a in metastatic RCC
10mg/kg every 2 weeks (n638)
Combined with Xeloda? in previously treated
MBC 15mg/kg every 3 weeks (n462) Miller KD, et
al. 2005
Combined with TarcevaTM gemcitabine in
previously untreated PC 5mg/kg every 2
weeks (n600)
5-FU 5-fluorouracil LV leucovorin mCRC
metastatic colorectal cancer FOLFOX 5-FU/LV
oxaliplatin XELOX Xeloda oxaliplatinIFN
interferon CP carboplatin/paclitaxel CG
cisplatin/gemcitabine RCC renal cell cancer
MBC metastatic breast cancerIFL
irinotecan/5-fluorouracil/leucovorin NSCLC
non-small cell lung cancer PC pancreatic cancer
10
Bevacizumab with 5-FU/LV
11
Phase II trial of Avastin in mCRC (AVF0780g)
study design
5-FU/LV (n36)
High-dose Avastin (10mg/kg every 2 weeks)
PD
Previously untreated metastatic CRC
5-FU/LV Avastin (5mg/kg) (n35)
PD
5-FU/LV Avastin (10mg/kg) (n33)
PD

• Primary endpoints
• time to progression
• response rate
• i.v. 5-FU 500mg/m2 and LV 500mg/m2 were given
  weekly for the first 6 weeks of an 8-week cycle
  (Roswell Park regimen)
• Bevacizumab was given every 2 weeks
• Tumour assessments were at the end of each 8-week
  cycle

Kabbinavar F, et al. J Clin Oncol 200321605
12
Phase II trial of Avastin in metastatic CRC
(AVF0780g) time to progression
Avastin 5mg/kg (n35) Avastin 10mg/kg
(n33) Control (n36)
1.0 0.8 0.6 0.4 0.2 0
Median (months) Control 5.2 Avastin 5mg/kg 9.0
(HR0.46 p0.005) Avastin 10mg/kg 7.2(HR0.66
p0.217)
Proportion progression-free
5.2
7.2
9.0
0 2 4 6 8 10 12 14
Time to progression (months)
Blinded review by independent evaluators
Roche data on file
13
Phase II trial of Avastin in metastatic CRC
(AVF0780g) adverse events
All events Not adjusted for treatment duration
Kabbinavar F, et al. J Clin Oncol 200321605
14
Bevacizumab plus IFL (AVF2107g) in metastatic
CRC
15
Phase III trial of IFL Avastin in mCRC
(AVF2107g) study design
No Avastin past disease progression
Bolus IFL placebo(n411)
May receive Avastin past disease progression
Previously untreatedmetastatic CRC
Bolus IFL Avastin (n402)
Arm closed to enrolment
May receive Avastin past disease progression
5-FU/LV Avastin (n110)
IFLbolus 5-FU 500mg/m2LV 20mg/m2 irinotecan
125mg/m2 given 4/6 weeks
5-FU/LVbolus 5-FU 500mg/m2 LV 500mg/m2 given
6/8 weeks
Avastin5mg/kg every 2 weeks
Hurwitz H, et al. N Engl J Med 2004350233542
16
Phase III trial of IFL Avastin in mCRC
(AVF2107g) survival
Median survival (months)IFL placebo 15.6 (95
CI 14.317.0) vs IFL Avastin 20.3 (95 CI
18.524.2) HR0.66 (95 CI 0.540.81)plt0.001
1.0 0.8 0.6 0.4 0.2 0
IFL Avastin IFL placebo
Probability of survival
15.6
20.3
0 10 20 30 40
Survival (months)
CI confidence intervalHR hazard ratio
Hurwitz H, et al. N Engl J Med 2004350233542
17
Phase III trial of IFL Avastin in mCRC
(AVF2107g) PFS
Median progression-free survival (months)IFL
placebo 6.2 (95 CI 5.67.7)IFL Avastin
10.6 (95 CI 9.011.0) HR0.54 (95 CI
0.450.66) plt0.001
1.0 0.8 0.6 0.4 0.2 0
Probability of being progression free
IFL Avastin IFL placebo
6.2
10.6
0 10 20 30
Progression-free survival (months)
Hurwitz H, et al. N Engl J Med 2004350233542
AVF2107g
18
Phase III trial of IFL Avastin in mCRC
(AVF2107g) Avastin-related toxicity
NB not adjusted for different time on
therapy plt0.05
Hurwitz H, et al. N Engl J Med 2004350233542
19
First-line Phase II trial of Avastin 5-FU/LV
in mCRC (AVF2192g)

• Multicentre, double-blind, randomised, controlled
  trial in 209 patients not eligible for first-line
  irinotecan

5-FU/LV (n105)
PD
Previously untreated metastatic CRC (n209)
5-FU/LV Bevacizumab 5mg/kg every 2 weeks
(n104)
PD
Primary endpoint duration of survival Secondary
endpoints include overall response rate
Kabbinavar FF, et al. J Clin Oncol
2005233697705
20

Phase II trial of Avastin 5-FU/LV in mCRC
(AVF2192g) survival
HR0.79, p0.160 vs control Median survival
12.9 vs 16.6 months
1.0 0.8 0.6 0.4 0.2 0
5-FU/LV Avastin 5-FU/LV placebo
Probability of survival
12.9
16.6
0 10 20 30 40
Duration of survival (months)
Kabbinavar FF, et al. J Clin Oncol
2005233697705
AVF2192g
21
Phase II trial of Avastin 5-FU/LV in mCRC
(AVF2192g) progression-free survival
1.0 0.8 0.6 0.4 0.2 0
HR0.50, p0.0002 vs control Median
progression-free survival 5.5 vs 9.2 months
Probability of being progression free
5-FU/LV Avastin 5-FU/LV placebo
5.5
9.2
0 10 20 30
Progression-free survival (months)
Kabbinavar FF, et al. J Clin Oncol
2005233697705
22
Phase II trial of Avastin 5-FU/LV in mCRC
(AVF2192g) Avastin-related toxicity
NB not adjusted for different time on therapy
Kabbinavar FF, et al. J Clin Oncol
2005233697705
23
FDA Approval
BEVACIZUMAB used in combination with intravenous
5-FUbased chemotherapy, is indicated for
first-line treatment of patients with metastatic
carcinoma of the colon or rectum.
24
Avastin plus FOLFIRI
25
Phase II trial of Avastin plus FOLFIRI (AVIRI)
study design
Patients with previously untreated metastatic CRC
(n209)
Avastin 5mg/kg every 2 weeks FOLFIRI

• Primary endpoint progression-free survival
• Secondary endpoints overall survival, overall
  response rate, duration of response and safety
• Recruitment complete

Sobrero A, et al. J Clin Oncol 200624157s
(Abstract 3544)
26
Phase II trial of Avastin plus FOLFIRI (AVIRI)
efficacy
The incidence of Bevacizumab related side effects
appears to be generally similar to that in other
Beva-trials Estimated 6 month progression free
survival rate is 82
Sobrero A, et al. J Clin Oncol 2006 24 157s
(Abstract 3544)
27
Phase II trial of Avastin plus FOLFIRI (US)
preliminary results

• Phase II trial of Avastin (5mg/kg every 2 weeks)
  plus FOLFIRI in 23 patients with metastatic CRC1

Observed at a median of 4.1 (2.28.0) months
Generally well tolerated less diarrhoea and
hospitalisations than that observed with IFL plus
Avastin similar level of hypertension and
proteinuria
1Kopetz S, et al. J Clin Oncol 200624165s
(Abstract 3579)
28
Avastin plus Capecitabine alone or combo
CAPIRI/XELIRI
29
Preclinical evidence for the use of Avastin with
Xeloda-based therapy

• Combining Avastin and Xeloda resulted in a
  greater duration of tumour inhibition than with
  either agent alone

2,000 1,750 1,500 1,250 1,000 750 500 250 0
Control Avastin Xeloda Avastin Xeloda
Mean tumour volume (mm3)
0 7 14 21 28 35 42 49 56 63
Day
Sub-maximum effective doses
Shen BQ, et al. Proc AACR 200445 (Abstract 2203)
30
Ongoing/planned trials of Xeloda plus Avastin in
first-line mCRC

• MAX (ML18513) randomised phase II/III trial
  (n333)
• patients with previously untreated metastatic CRC
  will be randomised to receive one of three
  regimens until disease progression
• Xeloda
• Avastin 7.5mg/kg every 3 weeks plus Xeloda
• Avastin 7.5mg/kg every 3 weeks plus Xeloda plus
  mitomycin C
• Several other trials of Avastin plus Xeloda are
  planned, including
• ML18524, open label study comparing the effect of
  three chemotherapy regimens (n300)
• ML18799, phase II trial (n80)
• ML19823, phase II trial in elderly patients (n60)

31
Phase I/II trial of Avastin plus Xeloda and
irinotecan (XELIRI)
Patients (n14) were treated with Avastin
7.5mg/kg every 3 weeks plus XELIRI 13 patients
are evaluable for response

• Therapy was well tolerated
• epistaxis was reported in one patient,
  proteinuria lt1g/day in two patients and
  granulocytopenia grade 3 in one patient

Kocakova I, et al. J Clin Oncol 200624616s
(Abstract 13504)
32
Avastin withoxaliplatin-based regimens
33
Phase III trial of second-line Avastin plus
FOLFOX4 (E3200) study design
Oxaliplatin/5-FU/LV (n290)
PD
Oxaliplatin/5-FU/LV Avastin 10mg/kg every2
weeks(n289)
Previously treated metastatic CRC (n822)
PD
Avastin monotherapy 10mg/kg every 2 weeks(n243)
Arm closed to enrolment
PD

• Primary endpoint duration of survival
• Secondary endpoint overall response rate
• Exclusion criteria CNS metastases active
  cardiovascular disease

Giantonio BJ, et al. J Clin Oncol 2005231s
(Abstract 2)
34
Phase III trial of second-line Avastin (E3200)
progression-free survival
1.0 0.8 0.6 0.4 0.2 0
HR0.64 A vs B plt0.0001 B vs C plt0.0001
A FOLFOX4 Avastin
C Avastin
B FOLFOX4
Probability of being progression free
2.7
7.2
4.8
0 2 4 6 8 10 12 14 16 18 20
Progression-free survival (months)
Median
Total
273
7.2
A FOLFOX4 Avastin
273
4.8
B FOLFOX4
229
2.7
C Avastin
Giantonio BJ, et al. J Clin Oncol 2005231s
(Abstract 2)
35
Phase III trial of second-line Avastin (E3200)
overall survival
1.0 0.8 0.6 0.4 0.2 0
HR0.76 A vs B p0.0018 B vs C p0.95
A FOLFOX4 Avastin
C Avastin
B FOLFOX4
HR hazard ratio
Probability of survival
10.8
10.2
12.9
0 3 6 9 12 15 18 21 24 27 30 33 36
Time (months)
Median
Total
A FOLFOX4 Avastin
289
12.9
B FOLFOX4
290
10.8
C Avastin
243
10.2
Giantonio BJ, et al. J Clin Oncol 2005231s
(Abstract 2)
36
Phase III trial of second-line Avastin (E3200)
grade 3/4 toxicity
Giantonio BJ, et al. J Clin Oncol 2005231s
(Abstract 2)
37
Phase III study ongoing XELOX bevacizumab vs
FOLFOX4 bevacizumab (NO16966C)

• Factorial study 2 x 2

Bevacizumab 5 mg/kg every 2 weeks (n330)
PRO
FOLFOX4 (n300)
Previously untreated metastatic CRC (n1920)
Placebo (n330)
PRO
Bevacizumab 7,5 mg/kg every 3 weeks (n330)
PRO
XELOX (n300)
Placebo (n330)
PRO
Primary endpoints Time to progression with XELOX
( bevacizumab) equivalent to FOLFOX4 (
bevacizumab) Time to progression with bevacizumab
XELOX/FOLFOX superior to XELOX/FOLFOXplacebo
Cassidy J. ESMO 2006 Saltz LB ASCO GI 2007
38
Ongoing phase III trial of XELOX Avastin vs
FOLFOX4 Avastin (NO16966C) preliminary data
Cassidy J. ESMO 2006 Saltz LB ASCOGI 2007

• HR 0.70 97.5 CI 0.580.83
• p lt 0.0001

1.0 0.8 0.6 0.4 0.2 0.0

• The study met both primary endpoints
• XELOX FOLFOX4
• as similar activity in terms
• of PFS
• Bevacizumab XELOX or FOLFOX4 significantly
  improved PFS compared with chemotherapy alone
• No new safety signals related to Beva have been
  reported

PFS estimate
8.5
11.5
10
0
5
15
20
25
XELOX / FOLFOX bevacizumab 289 events XELOX /
FOLFOX placebo 347 events
39
TREE-2 phase II trial of first-line with various
oxaliplatin-based regimens
mFOLFOX6 Avastin5mg/kg every 2 weeks (n75)
PD
bFOL Avastin 5mg/kg every 2 weeks (n74)
First-line metastatic CRC (n223)
PD
XELOX Avastin7.5mg/kg every 3 weeks (n74)
PD
Primary endpoint grade 3/4 toxicity during the
first 12 weeks of therapy Secondary endpoints
include overall response rate, time to
progression and overall survival
Hochster HS, et al. J Clin Oncol 200624148s
(Abstract 3510)
40
TREE-1 versus TREE-2 TTP
TREE-1
TREE-2
1.0
1.0
mFOLFOX bFOL XELOX
mFOLFOX Avastin bFOL Avastin XELOX Avastin
0.8
0.8
0.6
0.6
Probability
Probability
0.4
0.4
0.2
0.2
0
0
0
5
10
15
20
25
0
5
10
15
20
25
Months
Months
Hochster HS, et al. J Clin Oncol 200624148s
(Abstract 3510)
41
TREE-1 versus TREE-2overall survival
TREE-1
TREE-2
1.0
1.0
mFOLFOX Avastin bFOL Avastin XELOX Avastin
0.9
0.9
mFOLFOX bFOL XELOX
0.8
0.8
0.7
0.7
0.6
0.6
Probability
Probability
0.5
0.5
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
0
0
5
10
15
20
25
30
35
40
0
5
10
15
20
25
30
35
40
Survival time (months)
Survival time (months)
Hochster HS, et al. J Clin Oncol 200624148s
(Abstract 3510)
42
TREE-1 versus TREE-2 conclusions

• TREE-2 shows that combining Avastin with
  oxaliplatin-containing regimens is well tolerated
  and does not significantly alter the regimens
  toxicity profiles1
• The addition of Avastin to oxaliplatin-containing
  regimens improves response rates, TTP and OS
  compared to TREE-1
• XELOX tolerability improved with the lower Xeloda
  dose (850mg/m2 bid) used in TREE-2
• Bolus 5-FU-based regimens (bFOL) appear to be
  less active than infusional 5-FU (FOLFOX) or
  Xeloda-containing regimens

Hochster HS, et al. J Clin Oncol 200624148s
(Abstract 3510)
43
First-line randomised phase II Avastin XELIRI
or XELOX in mCRC AIO study preliminary data
ML18405 trial
XELOX Bevacizumab 7.5mg/Kg, arm A
Previously untreated metastatic CRC
XELIRI Bevacizumab 7.5mg/Kg, arm B
Conclusions In pts with untreated mCRC, both
regimens, XELOXB and XELIRIB are well-tolerated
without difference for severe AE in both
treatment arms (except neuropathy) and can be
safely administered on an outpatient basis. So
far, both regimens show similarly high tumor
control and response rates.
M. Geissler. Et al. ASCO GI 2007 abs335
44
Avastin in first-line treatment of metastatic CRC
Metastatic CRC
Avastin
5-FU or Xeloda
First-line
IFL/FOLFIRI/XELIRI
FOLFOX or XELOX
Irinotecan cetuximab
FOLFOX
FOLFIRI
5-FU/LV
Second-line
BSC/FOLFOX/FOLFIRI
Avastin has shown consistent efficacy
improvements in metastatic CRC, regardless of the
regimen with which it is combined
45
Safety profile of Bevacizumab
46
Bevacizumab-related events in CRC trials to
date overview

• hypertension (most common event)
• proteinuria
• arterial thrombosis
• effects on wound healing
• bleeding
• GI perforation

Kabbinavar F, et al. J Clin Oncol
200321605 Hurwitz H, et al. N Engl J Med
2004350233542 Giantonio BJ, et al. ASCO GI
Symposium 2729 2005
Hollywood, Fl. Abstract
169a./www.asco.org. 2005. Kabbinavar FF, et al.
J Clin Oncol 2005..
47
Bevacizumab related toxicity
48
BRiTE US observation study First-BEAT
International observational study (ex-US)
49
BRiTE study overview
Previously untreated metastatic, locally
advanced and unresectable CRC (n1,968)
Avastin plus chemotherapy
PD

• Chemotherapy regimen and Avastin dose/schedule at
  investigator discretion
• Patients are followed for up to 3 years and
  clinical data updated every 3 months
• Objectives
• safety incidence of adverse events possibly
  related to Avastin
• efficacy time to progression, response rate and
  overall survival

BRiTE Bevacizumab Regimens Investigation of
Treatment Effects and Safety
Hedrick E, et al. J Clin Oncol 200624(Suppl.)15
5s (Abstract 3536)
50
First-BEAT study overview

• MO18024 study
• 381 centres in 41 participating countries
• Choice of chemotherapy at physicians discretion
• Patients are followed every 3 months
• Primary endpoint safety secondary endpoint
  efficacy
• First patient enrolled June 2004, enrolment
  complete February 2006

Standard 5-FU containing therapy Avastin
(5mg/kg every 2 weeks or 7.5mg/kg every 3 weeks)
Patients with previously untreated metastatic CRC
(1,927)
PD
BEAT Bevacizumab Expanded Access Trial
Berry S, et al. J Clin Oncol 200624(Suppl.)154s
(Abstract 3534)
51
mCRC Treated with Bevacizumab chemotherapy combo
Survival Results from the BRiTE registry
M. Kozloff, ASCO GI 2007 abs 66
52
Bevacizumab related toxicity
53
Therapeutical progress in metastatic Colorectal
cancer
median overall survival (months)
Supportive Care
Saltz NEJM 2000
12.6
5-FU bolus
Douillard Lancet 2000
14.1
Van Custem/Hoff JCO 2000
5-FU infusion
Irinotecan/5-FU bolus
Saltz NEJM 2000
14.8
17.4
Douillard Lancet 2000
Irinotecan/5-FU infusion
19.5
Oxaliplatin 5-FU infusion
Goldberg JCO 2004
Doulliard Lancet 2000
20.3
Hurwitz NEJM 2004
Irinotecan/5-FU bolus/bevacizumab
21.5
Tournigand JCO 2004
Irinotecan/5-FU inf. followed by oxaliplatin/inf.
5-FU
25.1
Irinotecan/5-FU bolus/bevacizumab followed by
oxaliplatin
Hurwitz NEJM 2004
FolFox/XeloX- bevacizumab
27,1
Kozloff ASCO GI 2007
Months
54
Avastin alone or in combination ongoing trials
55
DREAM study the intermittent chemotherapy
mFOLFOX7 x6
mFOLFOX7 x6
Avastin
Previously untreated pts with mCRC(n640)
mFOLFOX7 x6
mFOLFOX7 x6
Avastin
Avastin
Avastin Tarceva
XELOX4 x6
XELOX4 x6
Avastin
Avastin
Avastin Tarceva
Primary endpoint progression-free
survival Secondary endpoints overall survival
and duration of disease control mFOLFOX7 or
XELOX4 Avastin 5mg/kg every 2 wks Tarceva
100mg/day During chemotherapy pause Avastin
7.5mg/kg every 3 wks Tarceva 150mg/day
56
Ongoing phase IV optimisation trial (CONcePT) in
first-line mCRC
2x2 randomised, multicentre study
mFOLFOX7 Avastin INTERMITTENT oxaliplatin
intravenous Ca/Mg
Patients with metastatic CRC (n532)
mFOLFOX7 Avastin CONTINUOUS oxaliplatin treat-t
o-failure

• Primary endpoint time to treatment failure
• Secondary endpoints include toxicity and quality
  of life (QoL)

57
CALGB/SWOG 80405 Study design
Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2
once weekly
Patient/physician choice mFOLFOX6or FOLFIRI
Bevacizumab 5 mg/kg IV Every 2 wks
Patients with untreated mCRC (N 2289)
Cetuximab 400 mg/m2 IV Day 1, then 250 mg/m2 once
weeklyBevacizumab 5 mg/kg IV Every 2 wks
Primary endpoint OSSecondary endpoints PFS, RR
144 patients enrolled as of June 2006.
58
Avastin in the neoadjuvant setting
59
Neoadjuvant Avastin in patients with CRC single
centre, non-randomised trial patient
eligibility

• 5 cycles of XELOX Avastin every 2 weeks
• Avastin 5mg/kg day 1 Xeloda 3,500mg/m2/day days
  17 oxaliplatin 85mg/m2 day 1
• Sixth cycle of XELOX alone
• Patients undergo liver resection w/wo colon
  resection
• Avastin XELOX restarted 5 wks after surgery(6
  cycles)

A
A
A
A
A
SURGERY
XELOX
5 weeks
no treatment
Gruenberger B, et al. J Clin Oncol
200624(Suppl)157s (Abstract 3546)
60
Neoadjuvant Avastin in patients with CRC single
centre, non-randomised trial status

• 34 patients enrolled to date
• 19 patients have undergone surgery following
  Avastin XELOX
• remaining patients have not completed therapy
• 14/19 patients underwent liver resection alone
  and four had synchronous primary tumour resection
• one patient not resected due to extrahepatic
  disease
• 16 patients responded
• 3 complete responses, 13 partial response and 3
  stable disease

Gruenberger B, et al. J Clin Oncol
200624(suppl)157s (Abstract 3546)
61
Complication following hepatic surgery in pts
receiving neoadjuvant beva for CRC liver mts
Two subgroups of patients were identified, those
who received neoadjuvant BV and CTX (group 1) and
those who received neoadjuvant CTX only (group
2). There were 82 patients in group 1 and 45 in
group
These data suggest that the use of BV with
neoadjuvant CTX for pts with CRC liver metastases
is not associated with an increase in surgical
complications.
Kesmodel SB, et. Al. ASCO GI 2007 abs 234
62
Avastin in the adjuvant setting
63
Trials of Avastin in the adjuvant setting
NSABP The National Surgical Adjuvant Breast and
Bowel Project
64
AVANT study design

• Randomised, open-label study

FOLFOX4
Observation
Avastin alone (7.5mg/kg every 3 weeks)
Surgery for high risk stage II stage III colon
cancer (n3,450)
FOLFOX4 Avastin (5mg/kg every 2 weeks)
XELOX Avastin (7.5mg/kg every 3 weeks)
Avastin alone (7.5mg/kg every 3 weeks)
Duration of treatment phases
24 weeks
24 weeks

• Primary endpoint disease-free survival
• Secondary endpoints overall survival and safety

65
NSABP C-08 study design
Observation
mFOLFOX6 alone
Dukes C colon cancer (n2,714)
mFOLFOX6 Avastin 5mg/kg every 2 weeks
Avastin 5mg/kg every 2 weeks
24 weeks
24 weeks

• Primary endpoint disease-free survival
• Secondary endpoints include survival and
  tolerability
• Trial design
• 90 power for 25 reduction in risk of
  progression after 5 years
• 82 power for 25 reduction in risk of death
  after 7 years

66
Conclusive considerations

• Bevacizumab improves OS, PFS and RR, when used in
  combination with standard chemotherapy regimens
  in pts with mCRC
• Bevacizumab-containing regimens are well
  tolerated and does not significantly alter the
  regimens toxicity profiles
• Bevacizumab therapy is the essential basis of
  first-line treatment regimens
• Beva-monotherapy after irinotecan or oxaliplatin
  chemotherapy is warrant of further evaluation
• Interesting the beva-capecitabine combination in
  mCRC
• No mature date for adjuvant or neoadjuvant
  therapeutical modality with bevacizumab

67
The End

• Stop Here

68
BRiTE first-line chemotherapyregimens used on
study
60 50 40 30 20 10 0
Patients ()
IFL
FLOX
Other
Bolus5-FU/LV
XELOX
FOLFIRI
FOLFOX
Infusional5-FU/LV
FOLFIRI 5-FU/LV irinotecan XELIRI Xeloda
irinotecan IROX irinotecan oxaliplatin
FLOX 5-FU/LV oxaliplatin
Hedrick E, et al. J Clin Oncol 200624(June 20
Suppl.)155s (Abstract 3536)
69
First-BEAT most commonly usedchemotherapy
regimens
30 25 20 15 10 5 0
5-FU bolus 8 5-FU infusion 59 Xeloda 30 Other
3
Percentage ()
Monotherapy Oxaliplatin Irinotecan Other/missing
(15) (48) (33) (3)
Berry S, et al. J Clin Oncol 200624(Suppl.)154s
(Abstract 3534)
70
CONcePT intermittent oxaliplatin

• Stage 1
• Avastin 5mg/kg
• CI 5-FU/LV
• Oxaliplatin 85mg/m2
• Stage 2
• Avastin 5mg/kg
• CI 5-FU/LV
• Stage 3
• Avastin 5mg/kg
• CI 5-FU/LV
• Oxaliplatin 85mg/m2

x8 cycles, months 14 Oxaliplatin 680mg/m2
??????
x8 cycles, months 58
x8 cycles, months 912 Oxaliplatin 1,360mg/m2
CI continuous infusion Cumulative dose
71
Commonly expressed oncogenes influence VEGF
expression
adapted from Kerbel R, et al. Nat Rev Cancer
2002272739
72
Correlation of VEGF expression with metastatic
disease
100 80 60 40 20 0
93
13/14
Patients with metastases ()
34
10/29
5
1/19
01 2 3
Intensity of VEGF staining
n62
Takahashi Y, et al. Cancer Res 19955539648
73
Proteinuria
??????

• Proteinuria is a common event occurring in 23.3
  of all Bevacizumab-treated patients
• majority has been grade 1 proteinuria
• Grade 3 proteinuria and nephrotic syndrome are
  rare
• events are possibly linked to hypertension
• Improves after Bevacizumab treatment is stopped
• Recommendations
• proteinuria should be monitored by dipstick
  urinalysis prior to starting and during
  Bevacizumab therapy
• therapy should be stopped in patients with grade
  4 proteinuria (nephrotic syndrome)

Bevacizumab Summary of Product Characteristics
74
Arterial thromboembolic events results of a
pooled analysis
??????

• Independent risk factors for arterial
  thromboembolic events included
• history of prior arterial thromboembolic events
  such as stroke or heart attack
• age of 65 years or older
• Arterial events included in analysis
• CVA (stroke), transient ischaemic attack,
  subarachnoid haemorrhage
• myocardial infarction, angina (unstable angina),
  arterial thrombosis and other arterial
  thromboembolic events

CVA cerebral vascular accident Pooled analysis
of five randomised trials
Roche data on file
75
Bleeding
??????

• Patients treated with Bevacizumab may have an
  increased risk of developing tumour-associated
  haemorrhage
• Epistaxis is the most common bleeding event
  associated with Bevacizumab in patients with
  metastatic CRC
• easily managed using standard first-aid
  techniques
• Bevacizumab is contraindicated in patients with
  untreated CNS metastases
• Recommendations
• Bevacizumab should be permanently discontinued in
  patients who experience grade 3 or 4 bleeding
  during therapy

Bevacizumab Summary of Product Characteristics
CNS central nervous system
76
Wound healing
??????

• Bevacizumab therapy may adversely affect the
  wound healing process
• Major surgical procedures in CRC patients treated
  with Bevacizumab may uncommonly lead to wound
  healing complications1,2
• No evidence that Bevacizumab increases the risk
  of complications in patients who have undergone
  surgery gt28 days prior to Bevacizumab therapy2
• Bevacizumab therapy should be discontinued3
• in patients who experience wound healing
  complications during therapy until the wound is
  fully healed
• for at least 28 days following major surgery or
  until the surgical wound is fully healed
• prior to elective surgery

1Hurwitz H, et al. J Clin Oncol 200422(July 15
Suppl.) Abstract 3702 2Scappaticci F, et al. J
Clin Oncol 200422(July 15 Suppl.) Abstract
3530 3Bevacizumab Summary of Product
Characteristics
77
GI perforation incidence and mortality rate
??????
1Kabbinavar FF, et al. J Clin Oncol 2005. In
press. 2Giantonio BJ, et al. J Clin Oncol
200422(July 15 Suppl.) Abstract 3017 3Giantonio
BJ, et al. Presented at 2005 Gastrointestinal
Cancers Symposium 2729 January 2005 Hollywood,
Fl. Abstract 169a. Available at
http//www.asco.org. Accessed 15 February 2005
4Hurwitz H et al. N Engl J Med 2004350233542
(Roche data on file)
78
SI PUO RIDURRE IL TEMPO DINFUSIONE NELLE PRIME
SOMMINISTRAZIONI?

• Simplification of bevacizumab (bev)
  administration Do we need 90, 60, or even 30
  minute infusion times?
• Administration of the initial dose of bev
  over 30 minutes appears to be safe and
  well-tolerated. This has been the standard
  initial infusion time at MSKCC for 5 mg/kg, 10
  mg/kg and 15 mg/kg doses of bev. Based on our
  favorable experience with 30 minute infusions of
  15 mg/kg (0.5 mg/kg/minute), as of Nov '05 we
  have changed our institutional guidelines such
  that all non-protocol patients receiving bev are
  initiated at the infusion rate of 0.5
  mg/kg/minute.

Saltz et al. Journal of Clinical Oncology, 2006
ASCO Annual Meeting Proceedings Part I. Vol 24,
No. 18S
79
Ongoing and planned trials of Avastin in CRC

• Data from ongoing and planned trials are expected
  to support and investigate
• optimisation of Avastin use with chemotherapy
• optimisation of chemotherapy use with Avastin
• incorporation of targeted agents with Avastin
• activity of Avastin across multiple lines of
  therapy
• first-line use is currently recommended to
  maximise benefit
• Studies are ongoing to examine continued efficacy
  after progression

80
??no

• Potential mechanisms of action of bevacizumab on
  tumor vasculature.
• Owing to high levels of proangiogenic molecules
  produced locally, such as VEGF, tumors make the
  transition from in situ carcinoma to frank
  carcinoma (1). At this stage, tumors become
  hypervascular, but the vessels are leaky and the
  blood flow is spatially and temporally
  heterogeneous. This leads to increased
  interstitial fluid pressure (IFP) and focal
  hypoxia, creating barriers to delivery and
  efficacy of therapeutics. The proposed mechanism
  of action of the VEGF-specific antibody
  bevacizumab is twofold
• inhibition of new-vessel formation and killing of
  immature tumor vessels (2)
• and transient normalization of the remaining
  vasculature by decrease in macromolecular
  permeability (and thus the IFP) and hypoxia, and
  improvement of blood perfusion (3).
• Another effect of bevacizumab may be the direct
  killing of cancer cells in subsets of tumors in
  which the cells express VEGF receptors.
• Regardless of the mechanisms involved,
  monotherapy with bevacizumab is not curative
  because it cannot kill all cancer cells, and in
  the longer term leads to a vasculature that is
  inefficient for drug delivery (4), and to tumor
  relapse using alternative pathways for
  neovascularization.