1. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer treated with FOLFIRI with or without cetuximab: The CRYSTAL experience
Eric Van Cutsem*
I Lang, G D’Haens, V Moieseyenko, J Zaluski, G Folprecht, S Tejpar, O Kisker, C Stroh, P Rougier
*University Hospital Gasthuisberg, Leuven, Belgium

2. Disclosure slide Research funding / advisory board: Amgen Merck KGaA
Novartis
Pfizer
Roche
Sanofi-Aventis

3. Epidermal growth factor receptor (EGFR) and KRAS
Khambata-Ford S, et al. J Clin Onc 2007;25:3230–7

4. Anti-EGFR antibodies in mCRC
3rd line
BOND: cetuximab ± irinotecan
NCIC C0.17: cetuximab vs BSC
Panitumumab vs BSC (KRAS wild-type)
2nd line
EPIC: irinotecan ± cetuximab
1st line
(Randomized) Phase II studies (chemo + cetuximab)
CRYSTAL: FOLFIRI ± cetuximab
PACCE: chemo/bevacizumab ± panitumumab
CAIRO2: capecitabine/oxaliplatin/bevacizumab ± cetuximab
Other phase III studies in progress

5. xx/xx/xxxx
Retrospective studies supporting the correlation between KRAS mutations and lack of response to EGFR inhibitors in chemorefractory mCRC
Reference
Treatment
No. of patients (wild-type:mutant)
Objective response n (%)
Wild-type
mutant
A Lièvre et al, (J Clin Oncol 2008)
Cetuximab ± CT
114 (78:36)
34 (44)
0 (0)
S Benvenuti et al, (Cancer Res 2007)
Panitumumab or cetuximab or Cetuximab + CT
48 (32:16)
10 (31)
1 (6)
W DeRoock, E Van Cutsem S Tejpar (Ann Oncol 2008)
Cetuximab or Cetuximab + irinotecan
113 (67:46)
27 (41)
D Finocchiaro et al, (ASCO Proceedings 2007)
81 (49:32)
13 (26)
2 (6)
F Di Fiore et al, (Br J Cancer 2007)
Cetuximab + CT
59 (43:16)
12 (28)
S Khambata-Ford et al, (J Clin Oncol 2007)
Cetuximab
80 (50:30)
5 (10)
RG Amado et al, (J Clin Oncol 2008)
Panitumumab
208 (124:84)
21 (17) 5
Editor: Presentation name here

6. First-line cetuximab + FOLFIRI: Correlation of KRAS status with efficacy
First-line treatment: cetuximab (6 weeks monotherapy), followed by cetuximab + FOLFIRI (n=52)
Cetuximab
Cetuximab + FOLFIRI
Outcome
Wild-type
Mutant
RR (CR+PR), %
27.6
55.2
31.6
p=0.015
p=0.144
Median PFS, months –
9.4
5.6
HR=2.12 p=0.0475
Tabernero J et al, ASCO GI 2008

7. CRYSTAL trial in first-line mCRC
Cetuximab + FOLFIRI
Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly + irinotecan (180mg/m2) + 5-FU (400 mg/m2 bolus mg/m2 as 46-hr continuous infusion) + FA every 2 weeks
EGFR-expressing metastatic CRC R
FOLFIRI
Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus mg/m2 as 46-hr continuous infusion) + FA every 2 weeks
Stratification factors
Regions
ECOG PS
Populations
Randomized patients n=1217
Safety population n=1202
ITT population n=1198
Van Cutsem E et al, ASCO 2007

8. CRYSTAL trial – Primary endpoint PFS ITT population independent review
Progression-free survival estimate
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Months
Cetuximab + FOLFIRI (n=599)
FOLFIRI (n-599) 2 4 6 8 10 12 14 16 18 20
Van Cutsem E et al, ASCO 2007

9. Cetuximab + FOLFIRI (n=599)
CRYSTAL trial - Secondary endpoint: Response rate (independent assessment - ITT) 60
p=0.0038a
FOLFIRI (n=599)
Cetuximab + FOLFIRI (n=599) % CR
0.3
0.5 PR
38.4
46.4 SD
46.7
37.4 PD
9.0
8.8
RR (CR+PR)
95% CI
38.7
[34.8 – 42.8]
46.9
[42.9 – 51.0] 50 47 40 39
Response rate (%) 30 20 10
FOLFIRI
Cetuximab + FOLFIRI
aCochran-Mantel-Haenszel (CMH) test
Van Cutsem E et al, ASCO 2007

10. KRAS analysis: Objective
A retrospective analysis investigated the impact on progression-free survival and response rate of the KRAS mutation status of tumors in the first-line treatment of metastatic CRC treated with FOLFIRI ± cetuximab

11. Relating KRAS status to efficacy
Efficacy analyses repeated on KRAS evaluable population
Genomic DNA isolated from archived tumor material
Paraffin-embedded, formalin-fixed tissue
KRAS mutation status of codons 12/13 determined using quantitative PCR-based assay

12. KRAS evaluable population
1198 subjects (ITT)
587 subjects analyzed for KRAS mutation status
540 (45%) subjects: KRAS evaluable population
348 (64.4%) KRAS wild-type
192 (35.6%) KRAS mutant
Group A: 172 (49.4%)
Group B: 176 (50.6%)
Group A: 105 (54.7%)
Group B: 87 (45.3%)
171 subjects with events (49.1%)
101 subjects with events (52.6%)
Cetuximab + FOLFIRI
FOLFIRI

13. Patient demographics at baseline according to KRAS status
xx/xx/xxxx
KRAS population
KRAS wild-type
n=348 %
KRAS mutant
n=192 %
Age <65
65.8
59.9
Gender, male
57.8
ECOG PS 0/1
96.6
97.9
Prior adjuvant therapy
21.6
12.5
Involved disease sites 2
85.3
83.3
Liver-limited disease
19.3
21.9 13
Editor: Presentation name here

14. ITT and KRAS evaluable population: Comparability
ITT population (n=1198) HR= mPFS Cetuximab + FOLFIRI: 8.9 months mPFS FOLFIRI: 8.0 months
Progression-free survival estimate
Months
0.5
1.0
0.4
0.3
0.2
0.1
0.6
0.7
0.8
0.9
0.0 8 2 4 6 10 12 14 16 18 20
KRAS population (n=540) HR= mPFS Cetuximab + FOLFIRI: 9.2 months mPFS FOLFIRI: 8.7 months
Cetuximab + FOLFIRI
FOLFIRI

15. Relating KRAS status to efficacy Primary endpoint: PFS – KRAS wild-type
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 2 4 6 8 10 12 14 16 18
Months
Progression-free survival estimate
Cetuximab + FOLFIRI
FOLFIRI
KRAS wild-type (n=348) HR=0.68; p= mPFS Cetuximab + FOLFIRI: 9.9 months mPFS FOLFIRI: 8.7 months
1-year PFS rate
25% vs 43%

16. Relating KRAS status to efficacy Primary endpoint: PFS – KRAS mutant
KRAS mutant (n=192) HR=1.07; p= mPFS Cetuximab + FOLFIRI: 7.6 months mPFS FOLFIRI: 8.1 months 2 4 6 8 10 12 14 16
Months
Cetuximab + FOLFIRI
FOLFIRI
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Progression-free survival estimate

17. Relating KRAS status to efficacy: PFS
Cetuximab + FOLFIRI HR=0.63; p= mPFS wild-type (n=172): 9.9 months mPFS mutant (n=105): 7.6 months
FOLFIRI HR=0.97; p= mPFS wild-type (n=176): 8.7 months mPFS mutant (n=87): 8.1 months
0.5
1.0
0.4
0.3
0.2
0.1
0.0
0.6
0.7
0.8
0.9 8 2 4 6 10 16
Progression-free survival estimate
Months
Cetuximab + FOLFIRI wild-type
Cetuximab + FOLFIRI mutant 12 14
0.5
1.0
0.4
0.3
0.2
0.1
0.0
0.6
0.7
0.8
0.9
Months
FOLFIRI wild-type
FOLFIRI mutant 8 2 4 6 10 16 12 14

18. Relating KRAS status to efficacy Secondary endpoint: Response – KRAS wild-type
p=0.0025a
FOLFIRI
Cetuximab + FOLFIRI
n=176 %
n=172 % CR
1.2 PR
43.2
58.1 SD
43.8
30.8 PD
9.1
5.2
RR (CR+PR)
59.3
95% CI
[35.8%, 50.9%]
[51.6%, 66.7%]
FOLFIRI
Cetuximab + FOLFIRI
aCochran-Mantel-Haenszel (CMH) test

19. Relating KRAS status to efficacy Secondary endpoint: Response – KRAS mutant
FOLFIRI
Cetuximab + FOLFIRI
n=87 %
n=105 % CR PR
40.2
36.2 SD
46.0
46.7 PD
8.0
9.5
RR (CR+PR)
95% CI
[29.9%, 51.3%]
[27.0%, 46.2%]
p=0.46a
FOLFIRI
Cetuximab + FOLFIRI
aCochran-Mantel-Haenszel (CMH) test

20. Relating KRAS status to outcome: Treatment exposure
5-FU
Irinotecan
Cetuximab
FOLFIRI
Cetuximab + FOLFIRI
KRAS wild-type
(n=176/173)
Median duration of treatment, weeks
28.9
32.0
30.0
Relative dose intensity ≥ 80% (%) 96 93 82 76 83
KRAS mutant
(n=87/105)
24.7
26.0
24.0
25.7 91 90 78 84

21. Relating KRAS status to outcome: Most common grade 3/4 adverse events
KRAS wild-type
KRAS mutant
FOLFIRI
n=176 %
Cetuximab + FOLFIRI
n=173 %
n=87 %
n=105 %
Any
50.6
78.0
55.2
72.4
Neutropenia
16.5
25.4
23.0
21.9
– Febrile neutropenia
0.6
3.8
Diarrhea
9.1
17.3
12.6
13.3
Vomiting
2.8
4.6
6.9
2.9
Fatigue
4.5
2.3
9.5
Acne-like rasha
16.2
17.1
Infusion-related reactions
1.7
aThere was no grade 4 acne-like rash

22. Summary of efficacy data
ITT
KRAS wild-type
KRAS mutant
FOLFIRI
Cetuximab + FOLFIRI
Cetuximab + FOLFIRI
(n=599)
(n=176)
(n=172)
(n=87)
(n=105)
RR (%) 39 47 43 59 40 36
p=0.0038a
p=0.0025a
p=0.46a
mPFS (months)
8.0
8.9
8.7
9.9
8.1
7.6 HR
0.85
0.68
1.07
p=0.048
p=0.017
p=0.75
aCochran-Mantel-Haenszel (CMH) test

23. Cetuximab + CT in KRAS wild-type: Data consistency
1.0
CRYSTAL - KRAS wild-type: HR=0.68
0.9
0.8
32% risk reduction for progression
0.7
0.6
PFS estimate
0.5
0.4
0.3
CRYSTAL
(n=540)
OPUS1 (n=233)
0.2
0.1
p=0.017
0.0 70 61 59 2 4 6 8 10 12 14 16 18
Months 60
1.0 50 43
OPUS - KRAS wild-type: HR=0.57
0.9 37
0.8
43% risk reduction for progression 40
0.7
Response rate (%)
0.6 30
PFS estimate
0.5
0.4 20
0.3 10
0.2
0.1
p=0.016
0.0
FOLFIRI
Cetuximab
+ FOLFIRI
FOLFOX
Cetuximab + FOLF0X 2 4 6 8 10 12
Months
1Bokemeyer C et al, ASCO 2008

24. CRYSTAL trial: Conclusions (1)
Adding cetuximab to FOLFIRI in mCRC leads to a significant increase in PFS (HR=0.85; p=0.048)
The benefit of cetuximab + FOLFIRI is greater in patients with KRAS wild-type tumors:
PFS (HR=0.68; p=0.017)
Response rate 59% vs. 43% (p=0.0025)
Patients with KRAS mutant tumors do not benefit from the combination of cetuximab and FOLFIRI
The grade 3/4 adverse event profile was similar in the KRAS wild-type and mutant populations

25. CRYSTAL trial: Conclusions (2)
KRAS is the first molecular marker for the selection of a targeted therapy in combination with a standard chemotherapy regimen in first-line mCRC
Patients with KRAS wild-type tumors have a strong benefit from the combination of cetuximab and FOLFIRI
Cetuximab in combination with a standard first-line treatment for mCRC patients is an important new option in patients with KRAS wild-type tumors

26. CRYSTAL trial: Acknowledgements
The authors would like to thank:
The patients
The investigators, co-investigators, and study teams at the 201 centers in 32 countries involved in this study
The study team at Merck KGaA, Darmstadt, Germany