1. Massimo Zeuli Oncologia Medica A Istituto Regina Elena Roma zeuli@ifo
Massimo Zeuli Oncologia Medica A Istituto Regina Elena Roma
"The best therapeutic approach to patients with KRAS wild type tumors" Roma 4 marzo 2011

3. 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. 3

4. 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
100
HR: (95% CI: )
P < .0001
HR: (95% CI: )
P = .48 80 80 60 60
Progression Free (%)
Alive (%) 40 40 20 20 2 4 6 8 10 12 2 4 6 8 10 12 14 16
Months
Months
Cunningham D, et al. N Engl J Med. 2004;351: Copyright © 2004 Massachusetts Medical Society. All rights reserved. 4

5. EPIC Study of Cetuximab in Second-Line mCRC: PFS
100
Cetuximab + irinotecan (n = 648)
Irinotecan (n = 650) 80 60
Median PFS: 4.0 months
Progression Free (%)
HR: 0.69 (95% CI: ) P ≤ .0001
Median PFS: 2.6 months 40 20 3 6 9 12 15 18
Months
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: Reprinted with permission from the American Society of Clinical Oncology 5

8. Panitumumab vs BSC in EGFR-Positive CRC: PFS Results
100 90
Panitumumab + BSC (n = 231)
BSC (n = 232) 80 70 60
Event Free (%)_ 50
HR: 0.54 (95% CI: )
P < .0001 40 30 20 10 8 16 24 32 40 48 56
Weeks
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: Reprinted with permission from the American Society of Clinical Oncology. 8

9. Panitumumab vs BSC in mCRC With Wild-Type K-ras: PFS Results
100 90
Panitumumab + BSC (n = 124)
BSC (n = 119) 80 70 60
Median PFS: 12.3 weeks
Progression Free (%) 50
HR: 0.45 (95% CI: )
P < .0001
Median PFS: 7.3 weeks 40 30 20 10 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: Reprinted with permission from the American Society of Clinical Oncology. 9

10. Panitumumab vs BSC in mCRC With Mutant K-ras: PFS Results
100 90
Panitumumab + BSC (n = 84)
BSC Alone (n = 100) 80 70 60
Median PFS: 7.4 weeks
Progression Free (%) 50
HR: 0.99 (95% CI: )
Median PFS: 7.3 weeks 40 30 20 10 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: Reprinted with permission from the American Society of Clinical Oncology. 10

11. Douillard J et al. JCO 2010;28:4697-4705
©2010 by American Society of Clinical Oncology

12. Pazienti kras wild type
Cetuximab/Panitumumab aumentano l’efficacia del trattamento chemioterapico

15. Pazienti kras wild type
Cetuximab/Panitumumab aumentano l’efficacia del trattamento chemioterapico
Bevacizumab aumenta l’efficacia del trattamento chemioterapico

16. Which regimen should we use as neoadjuvant treatment for liver metastases?
Pozzo C. et al Cancer Treat Rev, 2008

17. * * Of the 37 patients evaluable for
tumour KRAS mutation status, 81% had KRAS wild-type tumours.

18. Resection rates following targeted therapies plus chemotherapy in randomized trials
R0 resection rate
FOLFOX + ERBITUX
9.8
OPUS KRAS wt
FOLFOX
4.1
FOLFIRI + ERBITUX
9.8
CRYSTAL LLD
FOLFIRI
4.5
FOLFOX/XELOX + bevacizumab
12.3
NO LLD
p=NS
FOLFOX + XELOX
11.6 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

19. 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?

20. Massimo Zeuli Oncologia Medica A Istituto Regina Elena Roma zeuli@ifo
Massimo Zeuli Oncologia Medica A Istituto Regina Elena Roma ?
"The best therapeutic approach to patients with KRAS wild type tumors" Roma 4 marzo 2011

21. Pazienti k-ras wild-type,  chrono-IFLO+ 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).
FOLFOX4 x 3 mesi 
Chirurgia 
FOLFOX4 x 3 mesi
(studio EPOC - Lancet 2008):

22. C: Gruppo “ NON- RESECTABLE”
K-ras Wild Type
K-ras Mutant
1° Linea
FOLFIRI + BEVA
II° Linea
FOLFOX
III° Linea
Panitumumab
MMC + fluoro pirimidina*