Massimo Zeuli
Oncologia Medica A
Istituto Regina Elena
Roma
[email protected]
"The best therapeutic approach to
patients with KRAS wild type tumors"
Roma 4 marzo 2011
EGFR-Targeted Monoclonal Antibodies in mCRC
• Cetuximab
– IgG1 mAb
– Chimeric protein
• Panitumumab[1]
– IgG2 mAb
– Fully humanized
• Role of Kirsten-ras (K-ras)
mutation
1. Yang XD, et al. Crit Rev Oncol Hematol. 2001;38:17-23.
The BOND Study: Survival Data
• Addition of cetuximab to irinotecan improved the response
rate and time to progression but not overall survival
OS
Time to Progression
100
80
HR: 0.54
(95% CI: 0.42-0.71)
60
P < .0001
Alive (%)
Progression Free (%)
100
40
80
HR: 0.91
(95% CI: 0.68-1.21)
60
P = .48
40
20
20
0
0
0
2
4
6
8
Months
10
12
0
2
Cunningham D, et al. N Engl J Med. 2004;351:337-345. Copyright ©
2004 Massachusetts Medical Society. All rights reserved.
4
6
8 10
Months
12
14 16
EPIC Study of Cetuximab in
Second-Line mCRC: PFS
Progression Free (%)
100
Cetuximab + irinotecan (n = 648)
Irinotecan (n = 650)
80
60
40
Median PFS:
4.0 months
Median
PFS:
2.6 months
HR: 0.69 (95% CI: 0.62-0.78)
P ≤ .0001
20
0
0
3
6
9
Months
12
15
Sobrero AF, et al. EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and
Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer.J Clin Oncol. 2008;26:2311-2319.
Reprinted with permission from the American Society of Clinical Oncology
18
Panitumumab vs BSC in EGFR-Positive CRC:
PFS Results
100
90
Panitumumab + BSC (n = 231)
BSC (n = 232)
Event Free (%)_
80
70
60
50
HR: 0.54 (95% CI: 0.44-0.66)
P < .0001
40
30
20
10
0
0
8
16
24
32
Weeks
40
48
56
Van Cutsem E, et al. Open-label phase III trial of panitumumab plus best supportive care compared with
best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.J Clin
Oncol. 2007;25:1658-1664. Reprinted with permission from the American Society
of Clinical Oncology.
Panitumumab vs BSC in mCRC With Wild-Type K-ras: PFS
Results
100
Panitumumab + BSC (n = 124)
90
BSC (n = 119)
Progression Free (%)
80
70
60
Median PFS:
12.3 weeks
50
40
30
Median
PFS:
7.3 weeks
HR: 0.45 (95% CI: 0.34-0.59)
P < .0001
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Weeks
Amado R, et al. Wild-type KRAS is required for panitumumab efficacy in
patients with metastatic colorectal cancer.J Clin Oncol 2008;26:1626-1634.
Reprinted with permission from the American Society of Clinical Oncology.
Panitumumab vs BSC in mCRC With Mutant K-ras: PFS
Results
100
Panitumumab + BSC (n = 84)
90
BSC Alone (n = 100)
Progression Free (%)
80
70
60
Median PFS:
7.4 weeks
50
Median
PFS:
40
7.3 weeks
30
HR: 0.99 (95% CI: 0.73-1.36)
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52
Weeks
Amado R, et al. Wild-type KRAS is required for panitumumab efficacy in
patients with metastatic colorectal cancer.J Clin Oncol 2008;26:1626-1634.
Reprinted with permission from the American Society of Clinical Oncology.
Douillard J et al. JCO 2010;28:4697-4705
Pazienti kras wild type
 Cetuximab/Panitumumab aumentano
l’efficacia del trattamento chemioterapico
Pazienti kras wild type
 Cetuximab/Panitumumab aumentano
l’efficacia del trattamento chemioterapico
 Bevacizumab aumenta l’efficacia del
trattamento chemioterapico
Which regimen should we use as
neoadjuvant treatment for liver metastases?
Pozzo C. et al Cancer Treat Rev, 2008
*
* Of the 37 patients evaluable for
tumour KRAS mutation status, 81% had KRAS wild-type tumours.
Resection rates following targeted therapies plus
chemotherapy in randomized trials
NO16966 LLD CRYSTAL LLD
OPUS KRAS wt
R0 resection rate
9.8
FOLFOX + ERBITUX
4.1
FOLFOX
9.8
FOLFIRI + ERBITUX
4.5
FOLFIRI
FOLFOX/XELOX
+ bevacizumab
12.3
p=NS
11.6
FOLFOX + XELOX
0
2
4
6
8
10
12
14
Patients (%)
Van Cutsem E, et al. N Engl J Med 2009
Bokemeyer C, et al. J Clin Oncol 2009;27:663–671
Saltz LB et al. J Clin Oncol 2008
Pazienti kras wild type
 Cetuximab/Panitumumab aumentano
l’efficacia del trattamento chemioterapico
 Bevacizumab aumenta l’efficacia del
trattamento chemioterapico
 Cetuximab aumenta la percentuale di resezioni
epatiche R0?
Massimo Zeuli
Oncologia Medica A
Istituto Regina Elena
Roma
[email protected]
"The best therapeutic approach to
patients with KRAS wild type tumors"
Roma 4 marzo 2011
?
FOLFOX4 x 3 mesi 
Chirurgia 
FOLFOX4 x 3 mesi
(studio EPOC - Lancet 2008):
Pazienti k-ras wild-type,  chronoIFLO+ Cetuximab (Studio POCHER
Br J Cancer 2010). I pazienti che non
possono essere trattati con questo
schema e sono wild-type ricevono in
prima linea FOLFIRI + Cetuximab
(Studio Crystal N Engl J Med 2009).
C: Gruppo “ NON- RESECTABLE”
K-ras Wild
Type
K-ras Mutant
1° Linea
FOLFIRI +
BEVA
FOLFIRI +
BEVA
II° Linea
FOLFOX
FOLFOX
III° Linea
Panitumumab
MMC + fluoro
pirimidina*