1. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience
Authors: E. Van Cutsem, I. Lang, G. D'haens, V. Moiseyenko, J. Zaluski, G. Folprecht, S. Tejpar, O. Kisker, C. Stroh, P. Rougier

2. CRYSTAL Trial RANDOMI ZE FOLFIRI + Cetuximab FOLFIRI N=608 N=609
10 Endpoint= PFS
RANDOMI ZE
FOLFIRI + Cetuximab
N=608
N=1217
EGFR expression
via IHC
FOLFIRI
N=609
* Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly
1:1
Van Custem E Proc ASCO 2007

3. Results Efficacy Grade 3/4 toxicity FOLFIRI N = 650 (%)
FOLFIRI + Cetuximab
N = 648 (%)
Response Rate 39 47
Median PFS
8.0
8.9
1 yr PFS 23 34
Median OS NR
p=0.0038
HR = 0.85 ( ); p=0.048

4. Results Patient Characteristics
ITT
Centrally assessed for KRAS mutation by QT-PCR exon 12/13
n = 1198
n =540
Wild-type KRAS
(n=348)
Mutant KRAS
(n=192)
Male, %
57.8
Age < 65, %
65.8
59.9
Prior adjuvant Rx, %
21.6
12.5
Treatment, n (%)
FOLFIRI
FOLFIRI + Cetuximab
176 (51)
172 (49)
87 (45)
105 (55)

5. Results Efficacy Wild-type KRAS Mutant KRAS FOLFIRI FOLFIRI + Cetux
Median PFS, mos
8.7
9.9
8.1
7.6
1yr PFS rate, % 25 43 NR
ORR CR PR
43.2
59.3
1.2
58.1
40.2
36.2 SD
43.8
30.8
46.0
46.7
HR = 0.68; p 0.017
HR = 1.07; p 0.75
p 0.025
p 0.46

6. KRAS status and efficacy in the first-line treatment of patients with mCRC treated with FOLFOX with or without cetuximab: The OPUS experience
Authors: C Bokemeyer, I Bondarenko, J Hartmann, F De Braud, C Volovat, C Stroh,J Nippgen, I Celik, P Koralewski

7. OPUS: Phase II RANDOMI ZE FOLFOX + Cetuximab FOLFOX N=170 N=168 N=338
EGFR+
Metasatic CRC
FOLFOX
N=168
* Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly
1:1

8. Results Efficacy FOLFOX+ Cetuximab FOLFOX Response Rate 45.6% 35.7%
Median PFS, months
7.2

9. Results Patient Characteristics
ITT
Centrally assessed for KRAS mutation by QT-PCR exon 12/13
n = 337
n =233
Wild-type KRAS
(n=134)
Mutant KRAS
(n=99)
Male, %
55.2
49.5
Age < 65, %
63.4
62.6
Prior adjuvant Rx, %
18.7
17.2
Treatment, n (%)
FOLFOX
FOLFOX + Cetuximab
73 (54)
61 (46)
47 (47)
52 (53)

10. Results Efficacy Wild-type KRAS Mutant KRAS FOLFOX FOLFOX + Cetux
Median PFS, mos
7.2
7.7
8.6
5.5
1yr PFS rate, % NR
ORR CR PR
37.0
1.4
35.6
60.7
3.3
57.4
48.9
4.3
44.7
32.7 SD
16.4
4.9
36.2
51.9
HR = 0.57; p 0.016
HR = 1.83; p 0.019
p 0.011
p 0.11

11. Results Toxicity
No difference in skin rash or other toxicity by KRAS status in CRYSTAL or OPUS

12. STUDY COMMENTARY
Together with Panitumumab monotherapy in 3rd line setting (Van Custem JCO 2007) these two trials demonstrate that monoclonal antibody blockade against EGFR only benefit patients with wild-type KRAS
Similar findings with EGFR TKIs in NSCLC and pancreatic adenoCA
No overall survival data reported for either CRYSTAL or OPUS

13. Bottom Line for Canadian Medical Oncologists
Addition of Cetuximab to first line FOLFOX or FOLFIRI only benefits patients with wild type KRAS
Biologically plausible  mAb to receptor will not shut off signaling if a downstream kinase (KRAS) is constitutively active
Addition of Cetuximab to first line FOLFOX in KRAS mutant patients appears to be detrimental
? Biology of this phenomenon
Optimal sequence of biological therapy in KRAS wild-type patients remains to be determined
Should obtain KRAS mutational status on all patients where Cetuximab is considered
NCIC CO.17 is the only trial to demonstrate OS benefit with EGFR mAb
Retrospective survival analysis by KRAS status is eagerly awaited