bopa 2009 clinical update: colorectal cancer dr nick maisey
TRANSCRIPT
BOPA 2009
Clinical Update:
Colorectal Cancer
Dr Nick Maisey
Treatment Intent
Adjuvant Palliative
ADJUVANT CHEMOTHERAPY
Moertel et al, 1990 / 1995
CALGB 89803. Saltz et al ASCO 2004
ACCORD-2 Trial, Ychou et al ASCO 2005
PETACC-3, Van Cutsem, ASCO 2005
Irinotecan in Adjuvant Therapy
ACCORD-2: Ychou et al, ASCO 2005 PETACC 3: Van Cutsem et al, ASCO 2005
CALGB 89803: Saltz et al, ASCO 2004
Copyright © American Society of Clinical OncologyAndre, T. et al. J Clin Oncol; 27:3109-3116 2009
Overall survival (A) by treatment arm and (B) by treatment arm and by stage
Oxaliplatin: MOSAIC TrialFU/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
Adjuvant Biologics
Bevacizumab
Cetuximab
NSABP C-08
AVANT
QUASAR-2
PETACC-8
Intergroup 0147
NSABP C-08
RStage II / III
CRC
(n=2714)
FOLFOX 6/12
FOLFOX 6/12
AVASTIN 12/12
Wolmark et al, JCO 2009
NSABP-C08
3Y DFS 1.0 1.5 2.0 2.5 3.0
FOLFOX 75.5%
(n=1338)
0.6 0.74 0.81 0.85 0.87
0.0004 0.004 0.02 0.05 0.08
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
Mo
nth
s
BSC5-FU
30
25
20
15
10
5
0
1. Cunningham, et al. Lancet 1998; 2. Van Cutsem, et al. BJC 20043. Rothenberg, et al. JCO 2003; 4. Hurwitz, et al. NEJM 2004
5. Karapetis, et al. NEJM 2008
Irinotecan1
Capecitabine2
Oxaliplatin3
Cetuximab5
Bevacizumab4
1980s 1990s 2000s 2009
BSC = best supportive care
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 BENEFITCONTINUED BENEFIT
Regressionof existing microvasculatureNormalisationof surviving microvasculature
Inhibitionof vessel regrowth and neovascularisation
First-Line Avastin and Irinotecan
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.
* p<0.001 Avastin + IFL vs IFL alone
4535 39
IFL +placebo1
(n=411)
Overall response rate (%)
Duration of response (months)
Median overall survival (months)*
Median progression-freesurvival (months)*
IFL +Avastin1
(n=402)
5-FU/FA +Avastin2
(n=110)
10.47.1 8.5
20.315.6 18.3
10.66.2 8.8
NO16966: XELOX ± Avastin vsFOLFOX ± Avastin in first-line mCRC
Initial two-arm
open-label study
(n=1 000)
Protocol amended to 2x2 placebo-controlled design after Avastin
Phase III data became available (n=1 400)
RecruitmentJune 2003 – May
2004 XELOX +placebo
n=350FOLFOX4 +
placebo n=351
XELOX + Avastinn=350
FOLFOX4 + Avastinn=349
XELOX n=317
FOLFOX4 n=317
RecruitmentFebruary 2004 – February
2005
Cassidy, et al. J Clin Oncol 2008Cassidy, et al. ASCO GI 2008
Saltz, L. B. et al. J Clin Oncol; 26:2013-2019 2008
Second Line FOLFOX-B
OS (months)
Est
ima
ted
pro
bab
ilit
y
FOLFOX4 + bevacizumab
FOLFOX4
1.0
0.8
0.6
0.4
0.2
0
Second-line2
Median OS10.8 vs 12.9 months(HR=0.75; p=0.0011)
0 10 20 30 40
12.910.8
Giantonio et al, JCO 2007
829pts pretreated with
5FU + Irinotecan
R
FOLFOX
(RR=8.6%)
FOLFOX-B
(RR=22.7%)
B
(RR=3.3%)
Duration of Treatment?
Bev No Bev
Hurwitz 40.4 wks 27.6 wks
Saltz 27.1 wks* 25.1 wks
*discontinuations for chemo tox
BRiTE:* continuation of bevacizumab post-
first progression significantly increases OS‡
Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008
*Non-randomised, observational trial‡Time from initiation of first-line treatment to death
OS (months)
12.6 19.9 31.8
Post-progression bevacizumabHR=0.48 (95% CI: 0.41–0.57)
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0.2
0
Est
imat
ed p
rob
abil
ity
p<0.001
Post-progression therapyBevacizumab post-PD (n=642)No bevacizumab post-PD (n=531)No treatment (n=253)
The EGFr Antibodies
Cetuximab In Irinotecan Refractory mCRC
CETUXIMAB + IRINOTECAN CETUXIMAB ALONE
Saltz 2001 Saltz 2004Cunningham 2003
22.5% 22.9% 10.8% 8.8%
(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
10 (31)
Reference Treatment
No. of patients (wild-type:
mutant)
Objective responsen (%)
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) 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)
Wild type rasMutant ras
KRAS mutation on PFS with panitumumab v BSC: a predictive marker
Amado et al, JCO 2008
NCIC CTG C0.17: Overall survival in NCIC CTG C0.17: Overall survival in K-rasK-ras Wild-Type patientsWild-Type patients
HR HR 0.550.55 95% CI (0.41,0.74)95% CI (0.41,0.74)
Log rank p-value:Log rank p-value: <0.0001<0.0001
Study armStudy arm MS MS (months)(months)
95% CI95% CI
Cetuximab + BSCCetuximab + BSC 9.59.5 7.7 – 10.37.7 – 10.3
BSC aloneBSC alone 4.84.8 4.2 – 5.54.2 – 5.5
Karapetis CS, et al. NEJM 2008; 359:17, 1757 -1765
0
0.2
0.4
0.6
0.8
1
0 2 4 6 8 10 12 14 16 18
Time from Randomisation (Months)
Pro
port
ion A
live
Cetuximab
BSC
CetuximabBSC
117 108 95 81 52 34 20 9 6 2113 92 69 36 24 17 12 5 3 3
Log rank p<0.001
Cetuximab used First-Line in KRAS w/t mCRC
CRYSTAL1 OPUS2
FOLFIRI
FOLFIRI-C
FOLFOX
FOLFOX-C
N=1217 / 540 N=337 / 233
med PFS 8.7 9.9 7.2 7.7
ORR 43% 59% 37% 61%
med OS 21.0 24.9 - -
(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 chemo-
resistant 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
No more than 3 mets
No extra-hepatic disease
Marathon runner fitness
Untreatable primary
Insufficient remant liver
Unresectable extra-hepatic disease
Progression through chemo
Resection rate of metastases and tumour response
Studies including nonselected patients with mCRC (solid line) (r=0.74; p<0.001)
Studies including selected patients(liver metastases only, no extrahepatic disease)(r=0.96; p=0.002)
Phase III studies including nonselected patients with mCRC (dashed line)(r=0.67; p=0.024)
Response rate0.90.80.70.60.50.40.3
Res
ecti
on
rat
e
0.6
0.5
0.4
0.3
0.2
0.1
0
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 tumoursR
esp
on
se r
ate
(%
)
0
10
20
30
40
50
60
70 CRYSTAL OPUS
n=176 n=73n=172 n=61
59
3743
61
Chemotherapy alone
CETUXIMAB + chemotherapy
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)
RO resection FOLFIRI vs FOLFIRI-C
1.7% vs 4.8%
Odds ratio 3.02 (p=0.002)
EMR 604-CELIM study
Adjuvant therapy for
6 cycles (same schedule as
pre-operatively)R
Patients with technically unresectable/
≥5 liver metastases without extrahepatic disease
ERBITUX +
FOLFOX
(n=56)
8 cycles (~4 months)
Technically
resectable
Primary endpoint: Response rate
4 further treatme
nt cycles
RESECTION
ERBITUX +
FOLFIRI
(n=55)
Technically
unresectable
Folprecht et al. ASCO GI 2009 Abstract no. 296
Response rates
FOLFOX6 + FOLFIRI + KRAS KRAS All
ERBITUX ERBITUX wild-type mutant patients
n=53 n=53 n=67 N=28 n=106*
CR/PR 68% 57% 70% 43% 62%
(36 pts) (30 pts) (47 pts) (12 pts) (66 pts)
95% CI 54-80% 42-70% 58-81% 24-63% 52-72%
SD 28% 30% 21% 46% 29%
(15 pts) (16 pts) (14 pts) (13 pts) (31 pts)
PD 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 response when combined with FOLFOX
1,2
100
80
60
40
20
0
Pat
ho
log
ical
res
po
nse
(%
)
1–8 cycles ≥9 cycles 1–8 cycles ≥9 cycles
FOLFOX FOLFOX + bevacizumab
Major responseComplete response
p=0.007
p=0.011
Pathological response predicts for survival2
Complete response: no residual cellsMajor response: 1–49% residual cellsMinor response: ≥50% residual cells 1. Zorzi, et al. ASCO GI 2009; 2. Blazer, et al. JCO 2008
NO16966: surgery with curative intentP
atie
nts
(%
) 6.1
8.4
12.9
19.2
(n=701) (n=699) (n=178) (n=177)
10
5
0
20
15
10
5
0
Pat
ien
ts (
%)
Placebo Avastin Placebo Avastin
ITT population Patients with liver metastases only
XELOX/FOLFOX4 + AvastinXELOX/FOLFOX4 + placebo
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