Transcript Document

BOPA 2009
Clinical Update:
Colorectal Cancer
Dr Nick Maisey
Treatment Intent
Adjuvant
Palliative
ADJUVANT
CHEMOTHERAPY
Moertel et al, 1990 / 1995
Irinotecan in
Adjuvant Therapy
89803: Saltz
Saltz et al,et
ASCO
CALGBCALGB
89803.
al 2004
ASCO 2004
PETACC 3: Van Cutsem et al, ASCO 2005
ACCORD-2: Ychou et al, ASCO 2005
ACCORD-2
Trial, Ychou et al ASCOPETACC-3,
Van Cutsem,
Oxaliplatin: MOSAIC Trial
FU/LV
FOLFOX
5Y DFS (III)
58.9%
66.4%
7.5%
p=0.005
5Y DFS (II)
79.9%
83.7%
3.8%
p=NS
5Y DFS (HRII) 74.6%
82.3%
7.7%
p=NS
6Y OS (III)
76%
78.5%
2.5%
p=0.045
6Y OS (II)
86.8%
86.9%
0.1%
p=NS
Overall survival (A) by treatment arm and (B) by treatment arm and by stage
Andre, T. et al. J Clin Oncol; 27:3109-3116 2009
Copyright © American Society of Clinical Oncology
Adjuvant Biologics
NSABP C-08
Bevacizumab
AVANT
QUASAR-2
Cetuximab
PETACC-8
Intergroup 0147
NSABP C-08
FOLFOX 6/12
Stage II / III
CRC
R
(n=2714)
FOLFOX 6/12
AVASTIN 12/12
Wolmark et al, JCO 2009
NSABP-C08
3Y DFS 1.0
FOLFOX
1.5
2.0
2.5
3.0
0.74 0.81
0.85
0.87
0.0004 0.004 0.02
0.05
0.08
75.5%
(n=1338)
0.6
FOLFOX-B 77.4%
(n=1334)
Adjuvant Summary
•
•
•
•
•
Most patients benefit from a FP
Irinotecan does not work
Oxaliplatin has small but significant OS effect
Data supports use of oral FP
No data to support Biologics
PALLIATIVE
CHEMOTHERAPY
Patient outcomes have improved with the
evolution of mCRC treatment options
Median OS
30
Months
25
20
15
10
5
0
1980s
1990s
2000s
2009
BSC
5-FU
Irinotecan1
Capecitabine2
Oxaliplatin3
Bevacizumab4
Cetuximab5
BSC = best supportive care
1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 2004
3. Rothenberg, et al. JCO 2003; 4. Hurwitz, et al. NEJM 2004
5. Karapetis, et al. NEJM 2008
What order to give the drugs?
Tournigand et al, JCO 2004
Survival and Access to 3 Drugs
Grothey et al, JCO 2004
Avastin: mechanism of action
EARLY BENEFIT
CONTINUED BENEFIT
Regressio
n
of existing
microvasculature
Normalisati
on
of surviving
microvasculature
Inhibition
of vessel regrowth and
neovascularisation
First-Line Avastin and Irinotecan
IFL +
placebo1
(n=411)
IFL +
Avastin1
(n=402)
5-FU/FA +
Avastin2
(n=110)
Overall response rate (%)
35
45
39
Duration of response (months)
7.1
10.4
8.5
Median overall survival (months)*
15.6
20.3
18.3
Median progression-free
survival (months)*
6.2
10.6
8.8
* p<0.001 Avastin + IFL vs IFL
alone
Adapted
from 1. Hurwitz H et al. N Engl J Med 2004;350(23):2335-42. 2. Hurwitz H et al. J Clin Oncol
2005;23(15):3502-8.
NO16966: XELOX ± Avastin vs
FOLFOX ± Avastin in first-line mCRC
Recruitment
June 2003 – May
2004
XELOX
n=317
FOLFOX4
n=317
Initial twoarm
open-label
study
(n=1 000)
Recruitment
February 2004 – February
XELOX + 2005 XELOX +
placebo
Avastin
n=350
n=350
FOLFOX4 +
FOLFOX4 +
placebo
Avastin
n=351
n=349
Protocol amended to 2x2 placebocontrolled design after Avastin
Phase III data became available
Cassidy, et al. J Clin Oncol 2008
(n=1 400)
Cassidy, et al. ASCO GI 2008
Saltz, L. B. et al. J Clin Oncol; 26:2013-2019 2008
Second Line FOLFOX-B
Second-line2
829pts
pretreated with
5FU + Irinotecan
Median OS
10.8 vs 12.9 months
(HR=0.75; p=0.0011)
0.8
FOLFOXB
(RR=8.6 B
%)
(RR=22.7
(RR=3.3
%)
%)
Estimated probability
FOLFOX4 + bevacizumab
R
FOLFOX
1.0
FOLFOX4
0.6
0.4
0.2
10.8
0
0
10
12.9
20
30
OS (months)
40
Giantonio et al, JCO
Duration of Treatment?
Hurwitz
Bev
40.4 wks
No Bev
27.6 wks
Saltz
27.1 wks*
25.1 wks
*discontinuations for chemo tox
BRiTE:* continuation of bevacizumab post‡
first progression significantly increases OS
Estimated probability
1.0
0.8
Post-progression therapy
Bevacizumab post-PD
(n=642)
No bevacizumab post-PD
(n=531)
No treatment (n=253)
0.6
Post-progression bevacizumab
(95% CI: 0.41–0.57)
0.4 HR=0.48
p<0.00
1
12.6
19.9
31.8
5
10
15
20
25
30
35
0.2 0
OS (months) Grothey, et al. ASCO 2007 (poster)
*Non-randomised, observational trial
‡Time
from initiation of first-line treatment to death
Grothey, et al. JCO 2008
The EGFr Antibodies
Cetuximab In Irinotecan Refractory mCRC
Saltz 2001
22.5%
Cunningham 2003
22.9%
CETUXIMAB + IRINOTECAN
Saltz 2004
10.8%
8.8%
CETUXIMAB ALONE
(1) Saltz et al, ASCO 2001
(2) Cunningham et al, NEJM 2004
(3) Saltz et al, JCO 2004
The role of KRAS
KRAS wild-type and EGFR inhibitor efficacy in
chemorefractory CRC: Response
Treatment
Reference
Objective response
No. of patients
n (%)
(wild-type:
mutant)
Wild-type Mutant
Lièvre A, et al. J Clin Oncol 2008
CETUXIMAB ± CT
114 (78:36)
34 (44)
0 (0)
Benvenuti S, et al. Cancer Res 2007
Panitumumab or
CETUXIMAB or
CETUXIMAB + CT
48 (32:16)
10 (31)
1 (6)
DeRoock W, et al. Ann Oncol 2008
CETUXIMAB or
CETUXIMAB +
irinotecan
113 (67:46)
27 (41)
0 (0)
Capuzzo F, et al. Br J Cancer 2008
CETUXIMAB ± CT
81 (49:32)
13 (26)
2 (6)
Di Fiore F, et al. Br J Cancer 2007
CETUXIMAB + CT
59 (43:16)
12 (28)
0 (0)
Khambata-Ford S, et al. J Clin Oncol 2007
CETUXIMAB
80 (50:30)
5 (10)
0 (0)
Amado RG, et al. J Clin Oncol 2008
Panitumumab
208 (124:84)
21 (17)
(0)
Karapetis CS, et al. NEJM 2008
CETUXIMAB + BSC
or BSC
287 (117:81) 15 (12.8)
1 (1.2)
KRAS mutation on PFS with panitumumab v
BSC: a predictive marker
Mutant ras
Wild type ras
Amado et al, JCO 2008
NCIC CTG C0.17: Overall survival in K-ras
1
Wild-Type patients
Study arm
MS
(months)
95% CI
Cetuximab + BSC
9.5
7.7 – 10.3
BSC alone
4.8
4.2 – 5.5
Proportion Alive
0.8
0.6
HR 0.55 95% CI (0.41,0.
Log
Log rank
rank p<0.001
p-value: <0.0001
0.4
0.2
Cetuximab
BSC
0
0
2
4
6
8
10
12
14
16
18
Time from Randomisation (Months)
Cetuximab 117
113
BSC
108
92
95
69
81
36
52
24
34
17
20
12
9
5
6
3
2
3
Karapetis CS, et al. NEJM 2008; 359:17, 1757 -1765
Cetuximab used First-Line in KRAS w/t mCRC
CRYSTAL1
OPUS2
N=1217 / 540
N=337 / 233
FOLFO
X
7.2
FOLFI
RI
8.7
FOLFIR
I-C
9.9
ORR
43%
59%
37%
61%
med OS
21.0
24.9
-
-
med PFS
FOLFOX
-C
7.7
(1) Van Cutsem et al, NEJM 2009
(2) Bokemeyer et al, JCO 2009
Palliative Chemotherapy: Summary
• Survival continues to improve
• Avastin appears to improve overall survival if used
‘optimally’
• Patients with mutated KRAS do not benefit from
cetuximab
• Cetuximab confers survival advantage in chemoresistant disease
• First line cetuximab improves PFS and RR
Neoadjuvant
Chemotherapy
Rationale
• ‘In-Vivo’ test of sensitivity
• Kill off microscopic disease
• Down-size to allow operability
Curing Metastatic Disease
Who is considered for curative liver
resection?
No Bilobar Disease
Untreatable primary
No more than 3
mets
Insufficient remant
liver
No extra-hepatic
disease
Unresectable extrahepatic disease
Marathon runner
fitness
Progression through
chemo
Resection rate of metastases and
tumour response
Resection rate
0.6
0.5
0.4
0.3
0.2
0.1
0
0.3
0.4
0.5
0.6
0.7
0.8
Response rate
0.9
Studies including
selected patients
(liver metastases only,
no extrahepatic
disease)
Studies
(r=0.96; p=0.002)
including
nonselected
patients with
Phase
studies includi
mCRC III
(solid
nonselected
patients
line)
with
mCRC (dashed line)
(r=0.74;
(r=0.67;
p<0.001)p=0.024)
Folprecht G, et al. Ann Oncol 2005;16:1311–1319
Survival after ‘down-sizing’ in initially
unresectable disease
Bismuth et al, Ann Surg 1996
Effect of Cetuximab in KRAS w/t tumours
CETUXIMAB + chemotherapy
Chemotherapy alone
70
CRYSTAL
OPUS
Response rate (%)
60
50
40
61
59
RO resection FOLFIRI vs
FOLFIRI-C
1.7% vs 4.8%
Odds ratio 3.02 (p=0.002)
43
37
30
20
10
0
n=176 n=172
n=73
n=61
1. Van Cutsem E, et al.: NEJM 360(14): 1408-17 (2009); 2. Bokemeyer C, et al.: J Clin Oncol 27(5): 663-671 (2009)
EMR 604-CELIM study
Patients with
technically unresectable/
≥5 liver metastases
without extrahepatic disease
R
RESECTI
ON
ERBIT
UX
Technicall
+
y
FOLF
resectable
ERBIT
OX
UX
(n=56)
Technicall
+
4
y
FOLFI
unresecta further
RI
treatme
ble
8(n=55)
cycles
nt
(~4 months)
cycles
Adjuvant therapy
for
6 cycles
(same schedule as
pre-operatively)
Primary endpoint:
Response rate
Folprecht et al. ASCO GI 2009 Abstract no. 296
Response rates
CR/PR
95% CI
SD
PD
FOLFOX6 +
FOLFIRI +
KRAS
KRAS
All
ERBITUX
ERBITUX
wild-type
mutant
patients
n=53
n=53
n=67
N=28
n=106*
68%
57%
70%
43%
62%
(36 pts)
(30 pts)
(47 pts)
(12 pts)
(66 pts)
54-80%
42-70%
58-81%
24-63%
52-72%
28%
30%
21%
46%
29%
(15 pts)
(16 pts)
(14 pts)
(13 pts)
(31 pts)
4%
13%
9%
11%
8%
(2 pts)
(7 pts)
(6 pts)
(3 pts)
(9 pts)
* 106 pts evaluable for efficacy
These are confirmed response rates
Folprecht et al. ASCO GI 2009 Abstract no. 296
Resection rates
FOLFOX6 +
FOLFIRI +
KRAS
All
ERBITUX
ERBITUX
wt
patients
n=53
n=53
N=67
n=106*
R0/R1 resect. /RFA
49%
43%
NR
46%
R0 resections
38%
30%
33%
34%
(20 pts)
(16 pts)
(22 pts)
(36 pts)
* 106 pts evaluable for efficacy
Folprecht et al. ASCO GI 2009 Abstract no. 296
Bevacizumab: significant pathological
1,2
response when combined with FOLFOX
Pathological response predicts for survival2
Major response
Complete response
Pathological response (%)
100
p=0.011
80
p=0.007
60
40
20
0
1–8 cycles
≥9 cycles
FOLFOX
Complete response: no residual cells
Major response: 1–49% residual cells
Minor response: ≥50% residual cells
1–8 cycles
≥9 cycles
FOLFOX + bevacizumab
1. Zorzi, et al. ASCO GI 2009; 2. Blazer, et al. JCO 2008
NO16966: surgery with curative intent
XELOX/FOLFOX4 + placebo
ITT population
XELOX/FOLFOX4 + Avastin
Patients with liver metastases only
10
20
19.2
8.4
Patients (%)
Patients (%)
15
6.1
5
12.9
10
5
0
0
Placebo
Avastin
Placebo
Avastin
(n=701)
(n=699)
(n=178)
(n=177)
Saltz, et al. WCGC 2007
Neoadjuvant Therapy: Summary
•
•
•
•
•
Metastatic disease can be cured
Higher response rates lead to higher resection rates
Cure depends on successful resection
Cetuximab increases reponse rate and R0 resections
Bevacizumab may augment neoadjuvant chemo