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Future directions for Avastin
in colorectal cancer (CRC)
®
Fairooz Kabbinavar
David Geffen School of Medicine at UCLA
Los Angeles, USA
Optimising Avastin in metastatic CRC:
ongoing clinical trial programme
The current clinical trial programme will generate additional
data with Avastin in combination with FOLFIRI, XELIRI,
FOLFOX and XELOX in metastatic CRC
Ongoing trials will provide further guidance regarding
• the true benefit of combining Avastin with oxaliplatin-containing
therapy
• how best to use Avastin with oxaliplatin-containing regimens given
the cumulative neurotoxicity of oxaliplatin
DREAM study
mFOLFOX7 x6
mFOLFOX7 x6
Avastin
Previously
untreated
patients with
metastatic CRC
(n=640)
mFOLFOX7 x6
Avastin
mFOLFOX7 x6
Avastin
Avastin +
Tarceva®
XELOX4 x6
XELOX4 x6
Avastin
XELOX4 x6
Avastin
Primary endpoint: progression-free survival
XELOX4 x6
Avastin +
Tarceva
Avastin
Secondary endpoints include overall survival, response rate, duration of disease control, tolerance and
quality of life
mFOLFOX7 or XELOX4: Avastin 5mg/kg every 2 weeks ± Tarceva 100mg/day
During chemotherapy pause: Avastin 7.5mg/kg every 3 weeks ± Tarceva 150mg/day
CONcePT: first-line metastatic CRC
phase IV optimisation
2x2 randomised, multicentre study
Patients with
metastatic CRC
(n=532)
mFOLFOX7 + Avastin
INTERMITTENT oxaliplatin
± intravenous
Ca/Mg
mFOLFOX7 + Avastin
CONTINUOUS oxaliplatin
‘treat-to-failure’
Primary endpoint: time to treatment failure
mFOLFOX = modified FOLFOX
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
*Cumulative dose
CI = continuous infusion
x8 cycles, months 1–4
Oxaliplatin 680mg/m2*
x8 cycles, months 5–8
x8 cycles, months 9–12
Oxaliplatin 1,360mg/m2*
OASIS - Oxaliplatin Avastin Sequence to
Investigate Survival: study design
First line
Patients
with
metastatic
CRC
(n=800)
Second/third line*
FOLFOX6 +
Avastin
(cycles 1–8)
FOLFIRI +
Avastin
PD
FOLFOX6
re-introduction
FOLFOX6 +
Avastin
(cycles 1–8)
5-FU/LV +
Avastin
PD
FOLFIRI
PD
PD
FOLFOX6
re-introduction
Primary endpoint: first progression-free survival
Secondary endpoints: duration of tumour control, overall survival and
neurotoxicity
Trial has 80% power to detect increase in progression-free survival from 10.5
to 14 months
*Avastin may be used second/third line
PD
Ongoing and planned trials of
Avastin in CRC
Trial
n
Treatment
NO16966
1,920 XELOX or FOLFOX ± Avastin
CALGB/SWOG
2,289 mFOLFOX6 or FOLFIRI +
Avastin, cetuximab or Avastin +
cetuximab
AVIRI
202
FOLFIRI + Avastin
ACCORD 13 (MEXICO)
144
XELIRI/FOLFIRI + Avastin
ML18524
300
Xeloda + Avastin vs
metronomic Xeloda + Avastin
vs XELIRI + Avastin
Avastin in the (neo)adjuvant setting
Rationale for Avastin in the
adjuvant setting
The role of angiogenesis and VEGF in colorectal tumour growth
is well established
Using anti-VEGF therapy such as Avastin when micrometastases
are dormant and potentially reliant on VEGF may prevent the
‘angiogenic switch’
Preclinical studies show that treatment with Avastin leads to
regression of human tumour xenografts,1–3 and a reduction in the
number and size of liver metastases in nude mice.4 Therefore,
Avastin may have a greater impact in earlier disease stages
1Gerber
HP, et al. Cancer Res 2000;60:6253–58
H, et al. Br J Cancer 2003;88:1979–86
3Shen BQ, et al. Proc Am Assoc Cancer Res 2004;45:508 (Abstract 2203)
4Warren RS, et al. J Clin Invest 1995;95:1789–97
2Wildiers
Adjuvant anti-VEGF therapy may prevent
the angiogenic switch
Premalignant
stage
Malignant
tumour
Tumour
growth
Vascular
invasion
Dormant
micrometastasis
(Avascular
tumour)
(Angiogenic
switch)
(Vascularised
tumour)
(Tumour cell
intravasation)
(Seeding in
distant organs)
Stages at which angiogenesis plays a role in tumour progression
Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:1207–25
A4.6.1 therapy and growth inhibition of
colorectal liver metastases in an animal model
Control
Control MAb (200µg)
Anti-VEGF MAb (10µg)
Anti-VEGF MAb (50µg)
Anti-VEGF MAb (100µg)
Anti-VEGF MAb (200µg)
Control MAb
1,600
Tumour volume (mm3)
A4.6.1
1,200
800
400
0
0
7
14
Time (days)
21
Warren RS, et al. J Clin Invest 1995;95:1789–97
Randomised, phase III trial of adjuvant Avastin
plus FOLFOX (AVANT): study design
Randomised, open-label study
Surgery for high risk
stage II + stage III
colon cancer
(n=3,450)
Duration of treatment phases:
FOLFOX4
Observation
FOLFOX4 + Avastin
(5mg/kg every
2 weeks)
Avastin alone
(7.5mg/kg every
3 weeks)
XELOX + Avastin
(7.5mg/kg every
3 weeks)
Avastin alone
(7.5mg/kg every
3 weeks)
24 weeks
24 weeks
Primary endpoint: disease-free survival
Secondary endpoints: overall survival and safety
XELOX = Xeloda® + oxaliplatin
AVANT: eligibility criteria
Histologically confirmed colon carcinoma
Tumour classification according to AJCC/UICC
 stage III
 stage II (high-risk population)
Potentially curative tumour resection within
28–56 days prior to starting treatment
ECOG performance status 1
AJCC = American Joint Commission on Cancer
UICC = International Union Against Cancer
ECOG = Eastern Cooperative Oncology Group
AVANT: study description
Primary endpoint: disease-free survival at 3 years for
stage III
 Statistical assumption: 80% power to demonstrate a 23% reduction
in the hazard ratio (72.2% vs 77.8%)
 2,880 stage III (960 per arm)
 570 stage II for exploratory analysis
 Recruitment period: 23 months, first patient included 21 December,
2004
 Multicentre: ~350 centres planned in 36 countries
First results expected in 2008
Study currently on hold for interim safety analysis
Other trials in the adjuvant setting
Trial
n
Cancer
Treatment
NSABP C-08
2,700
Colon
FOLFOX ± Avastin
E5202
3,282
Colon
FOLFOX ± Avastin
QUASAR2
3,510
Colon
Xeloda + Avastin vs
Xeloda
AVF3105s
TBD
Rectal
Avastin, 5-FU and
radiotherapy
NSABP = The National Surgical Adjuvant Breast and Bowel Project
XELIRI = Xeloda + irinotecan
Avastin in the neoadjuvant setting
The anti-angiogenic action of Avastin in preventing tumour
growth and metastasis, and potential synergistic activity
with radiotherapy, provides a strong rationale for use
earlier in the treatment of CRC
Avastin in the neoadjuvant setting may help reduce the size
of the tumour, making it resectable
Available data indicate that neoadjuvant therapy with
Avastin is feasible1
Several trials of Avastin in this setting are planned
Willett CG, et al. Nat Med 2004;10:145–7
Neoadjuvant Avastin in patients with
rectal cancer: phase I trial design
Patients with
primary and nonmetastatic rectal
cancer
Avastin 5mg/kg
2 weeks
Avastin 5mg/kg +
5-FU +
radiotherapy
Surgery
3 x 2-week
cycles
Assessment
Willett CG, et al. Nat Med 2004;10:145–7
Neoadjuvant Avastin in patients with rectal
cancer: outcomes after Avastin treatment
12 days after Avastin administration
• tumour regression of >30% in one patient
• no change in tumour size in five patients
Computed tomography (CT) scans (n=5) showed
• 40–44% decrease in tumour blood perfusion (n=4/5; p<0.05)
• 16–39% decrease in tumour blood volume (n=4/5; p<0.05)
• 25–59% reduction in tumour microvessel density (n=5/5; p<0.05)
All patients underwent subsequent surgery without peri- or
post-operative complications
Willett CG, et al. Nat Med 2004;10:145–7
100
Patient
1
17
90
3
16
4
80
5
70
6
60
50
PS (mL/min/100g tissue)
Blood flow
(mL/min/100g tissue)
Changes in tumour vasculature following a single
Avastin dose in patients with rectal cancer
15
14
13
12
11
40
10
30
9
Pretreatment
PS = permeability-surface area
Day 12
Pretreatment
Day 12
Willett CG, et al. Nat Med 2004;10:145–7
Changes in tumour vasculature following a single
Avastin dose in patients with rectal cancer (cont’d)
Day 12
20
22.5
16
18
IFP (mmHg)
Number of vessels per field
Pretreatment
12
8
13.5
9
4
4.5
0
0
1
3
4
Patient
IFP = interstitial fluid pressure
5
6
3
4
5
6
Patient
Willett CG, et al. Nat Med 2004;10:145–7
Trials of Avastin in the
neoadjuvant setting
Trial
Country/group
n
MO19051
Belgium/EORTC 108
Cancer
Treatment
Locally
Avastin,
advanced radiotherapy, Xeloda
rectal cancer ± oxaliplatin
ML18641
The
Netherlands
60
Rectal cancer Avastin and
radiochemotherapy
(Xeloda)
ML18522
Italy
80
Locally
Avastin and
advanced radiochemotherapy
rectal cancer (Xeloda)
MO18725
France
80
CRC liver
metastases
FOLFOX ± Avastin
EORTC = European Organisation for Research and Treatment of Cancer
Avastin plus targeted therapies
Rationale for combining
anti-VEGF and anti-HER1/EGFR agents
Both HER1/EGFR and VEGF are overexpressed in many tumours1
VEGF has been implicated in resistance to anti-HER1/EGFR therapy
Treatment with two agents targeting two different critical pathways may
be more effective than a single one2
Preclinical studies have shown that anti-VEGF and anti-HER1/EGFR
therapies have at least additive effects3
Clinical trials in various indications (RCC,4 NSCLC,5 HNSCC6) have shown
that the combination of Avastin® and TarcevaTM is active
HER = human epidermal growth factor receptor
EGFR = epidermal growth factor receptor
VEGF = vascular endothelial growth factor
RCC = renal cell cancer
NSCLC = non-small cell lung cancer
HNSCC = head and neck squamous cell carcinoma
1Viloria-Petit
A, et al. Cancer Res 2001;61:5090–101; 2Herbst RS, et al.
Eur J Cancer Suppl 2003;1:S293; 3Ciardiello F, et al. Clin Cancer
Res 2000;6:3739–47; 4Spigel DR, et al. J Clin Oncol 2005;23(June
1 Suppl.):387s (Abstract 4540); 5Sandler AB, et al. J Clin Oncol
2004;22(July 15 Suppl.): Abstract 2000; 6Vokes EE, et al. J Clin
Oncol 2005;23(June 1 Suppl.):501s (Abstract 5504)
0.75
DC101: Anti-VEGF receptor MAb
C225: Anti-EGFR MAb
GEO colon cancer xenograft
Control
VEGF-AS
MAbC225
0.50
0.25
0
Control
DC101
C225
DC101/
C225
Combination
Control-AS
2
Tumour volume (cm3)
Tumour weight (kg)
Experimental evidence for combined
EGFR and VEGF inhibition
1
0
0
20
40
60
80
100
Days
TMK-1 gastric cancer xenograft
MAb = monoclonal antibody
Jung YD, et al. Eur J Cancer 2002;38:1133–40
Ciardiello F, et al. Clin Cancer Res 2000;6:3739–47
Clinical data to support dual VEGF and
EGFR inhibition
Inter-trial analysis shows that Avastin plus cetuximab improves response
rate and time to progression in previously treated metastatic CRC patients
Cetuximab/
irinotecan
(historical)1
Cetuximab/
irinotecan/
Avastin2
Response rate (%)
23
37
0.03
Time to progression (months)
4.0
7.9
<0.01
Cetuximab alone
(historical)1
Cetuximab/
Avastin2
p value
Response rate (%)
11
20
0.05
Time to progression (months)
1.5
5.6
<0.01
2Saltz
1Cunningham
p value
D, et al. N Engl J Med 2004;351:337–45
LB, et al. J Clin Oncol 2005;23(June 1 Suppl.):248s (Abstract 3508)
Avastin with other
anti-HER1/EGFR agents in CRC
Trial
Cancer
Treatment
Primary
endpoint(s) Notes
Phase
n
PACCE
(Amgen)
III
~1,000
First-line FOLFOX or FOLFIRI + Avastin vs PFS
metastatic FOLFOX or FOLFIRI + Avastin +
CRC
panitumumab
Ongoing
US
intergroup
III
~2,500
First-line Chemotherapy + Avastin vs
metastatic chemotherapy + cetuximab vs
CRC
chemotherapy + Avastin +
cetuximab
PFS
Ongoing
CAIRO-2
III
750
Metastatic Avastin + XELOX vs
CRC
Avastin + XELOX + cetuximab
PFS
Planned
FOLFOX = 5-fluorouracil (5-FU)/leucovorin (LV) + oxaliplatin
FOLFIRI = 5-FU/LV + irinotecan
XELOX = Xeloda® + oxaliplatin
PFS = progression-free survival
Combinations with biological agents:
summary
Several agents targeting the VEGF pathway or EGFR
have received regulatory approval or are in the late
stages of clinical development for the treatment of
various cancer types
Evidence suggests that combined blockade of the two
pathways may provide better efficacy than blocking
either pathway alone
Avastin in multiple lines of treatment
First line
Second line
Avastin +
Avastin +
Avastin +
IFL / FOLFIRI
(XELIRI)
5-FU/LV
(Xeloda)
FOLFOX
(XELOX)
FOLFOX ±
Avastin
FOLFIRI /
FOLFOX ±
Avastin
FOLFIRI ±
Avastin
Cetuximab ±
irinotecan
Cetuximab ±
irinotecan
Cetuximab +
irinotecan
5-FU/LV
?
Cetuximab
Clinical trial
5-FU/LV = 5-fluorouracil/leucovorin; IFL/FOLFIRI = irinotecan, 5-FU/LV; FOLFOX = 5-FU/LV + oxaliplatin;
XELOX = Xeloda + oxaliplatin; XELIRI = Xeloda + irinotecan
Conclusions
Avastin is being evaluated in combination with all active
chemotherapy regimens, such as FOLFIRI, XELIRI, FOLFOX
and XELOX, to further optimise the treatment for
metastatic CRC
The potential of Avastin as an effective option in the
(neo)adjuvant setting is being evaluated in phase III
clinical trials
Ongoing trials are examining the efficacy and safety of
combining first-line Avastin with EGFR-targeted therapies in
patients with metastatic CRC