1. *University Hospital Gasthuisberg, Leuven, Belgium
The CRYSTAL trial: Efficacy and safety of irinotecan and 5-FU/FA with and without cetuximab in the first-line treatment of metastatic colorectal cancer
Eric Van Cutsem*, M Nowacki,
I Lang, S Cascinu,
I Shchepotin, J Maurel,
P Rougier, D Cunningham,
J Nippgen, C-H Köhne
*University Hospital Gasthuisberg, Leuven, Belgium

2. Cetuximab: mechanism of action
Epidermal growth factor receptor (EGFR) is expressed by most CRCs
Cetuximab is an IgG1 monoclonal antibody that:
Specifically targets EGFR with high affinity
Inhibits endogenous ligand binding thereby blocking dimerization, TK phosphorylation, and receptor-dependent downstream signaling
Induces antibody-dependent cell-mediated cytotoxicity (ADCC)

3. Phase I/II trials: cetuximab plus irinotecan in first line mCRC
+ 5-FU/LV/
irinotecan (IFL) 1
+ 5-FU/LV/ irinotecan (FOLFIRI)2
Cetuximab + 5-FU/LV/ irinotecan (AIO)3
No. of patients 29 42 21
Response rate (CR+PR)
48%
45%
67%
Stable disease (SD)
42%
38%
29%
Disease control
(CR+PR+MR+SD)
90%
83%
96%
Median survival (months) NA 23 33
1Rosenberg et al. ASCO 2002:Abstr 536; 2 Rougier et al, ASCO 2004:Abstr 3513; 3Folprecht et al. Ann Oncol 2006;17:

4. CRYSTAL trial: Study design
Cetuximab + FOLFIRI
Cetuximab IV 400 mg/m2 on day 1,
then 250 mg/m2 weekly + irinotecan (180mg/m2)
+ 5-FU (400 mg/m2 bolus +
2400 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 +
2400 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

5. CRYSTAL trial: Study endpoints
Primary endpoint:
Progression-free survival time (as assessed by blinded independent review)
Secondary endpoints:
Overall response rate (independently reviewed)
Disease control rate (CR+PR+SD)
Overall survival time
Quality of life (EORTC QLQ C30)
Safety

6. CRYSTAL trial: Statistical considerations
Assumption for sample size calculation:
633 events (documented PDs) required to detect a hazard ratio of 0.8 with 80% power
Protocol required a sample size of 1080 patients
A central stratified permuted block randomization procedure was used with regions (Western Europe, Eastern Europe, Rest of World) and ECOG PS (0/1, 2) as randomization strata
Two interim assessments of safety data were conducted by an independent DSMB
Assessments were performed every 8 weeks

7. CRYSTAL trial: Main inclusion criteria
Histologically confirmed unresectable mCRC
EGFR expression in primary tumor or metastasis as detected by IHC
≥ 1 bi-dimensionally measurable lesion
No previous chemotherapy for metastatic disease; adjuvant therapy was allowed if stopped at least 6 months before randomization (no irinotecan)
ECOG PS ≤ 2 at study entry
Adequate organ and bone marrow function
Signed informed consent

8. CRYSTAL trial: Patient baseline characteristics (1)
ITT population
FOLFIRI
n=599
Cetuximab
+ FOLFIRI
Median age, years
[range] 61
[ ]
[ ]
Gender, %
Male
Female 59 41 62 38
ECOG PS, % 1 2 53 43 4 55
Tumor localization, %
Colon
Rectum
Colon and rectum 60

9. CRYSTAL trial: Patient baseline characteristics (2)
ITT population, %
FOLFIRI
n=599
Cetuximab
+ FOLFIRI
Adjuvant chemotherapy 17 19
Radiotherapy pre-treatment 12 11
No. metastatic sites
≤ 2 83 86
Liver metastases only 22 20
LDH
> UNL 45
Alk. Phosph.
≥ 300 U/L 13
Leucocytes
> 10,000/mm3 16

10. CRYSTAL trial: Safety: Grade 3/4 AE
FOLFIRI
n=602, %
Cetuximab + FOLFIRI
n=600, %
Any
59.5
78.0
Neutropenia
23.3
26.7
Febrile neutropenia
2.2
2.7
Diarrhea
10.5
15.2
Vomiting
5.0
4.5
Fatigue
Skin reactionsa
0.2
18.7
Infusion-related reactions
2.3
aThere were no grade 4 skin reactions
Magnesium levels were measured in only 20% of the patients (0.2% vs. 1.8%)

11. CRYSTAL trial: Reasons for treatment discontinuation
*SD=symptomatic deterioration

12. CRYSTAL trial: Deaths on study
FOLFIRI
n=602, %
Cetuximab + FOLFIRI
n=600, %
All deaths within 60 days after treatment start
3.0
3.2
All deaths from treatment start to 30 days after end of treatment
- of these treatment-related*
4.3
1.0
5.5
0.8
*No deaths were cetuximab-related

13. Progression-free survival time (months)
CRYSTAL trial: Primary endpoint PFS met ITT population independent review
1.0
FOLFIRI, n=599
Cetuximab + FOLFIRI, n=599
0.8
0.9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
HR = 0.851; 95% CI = [ ]
Stratified log-rank p-value =
8.9 mo
PFS estimate
1-year PFS rate
23% vs 34%
8.0 mo 2 4 6 8 10 12 14 16 18 20
Subjects at risk
FOLFIRI alone
599
492
402
293
178 83 35 16 7 4 1
Cetuximab +
FOLFIRI
499
392
298
196
103 58 29 12 5
Progression-free survival time (months)

14. CRYSTAL trial: Independent assessment of response
FOLFIRI %
Cetuximab
+ FOLFIRI CR PR SD PD
0.3
38.4
46.7
9.0
0.5
46.4
37.4
8.8
ORR
95%CI
38.7
[ ]
46.9
[ ]
DCR**
85.5
84.3
p-value* =
*Cochran-Mantel-Haenszel (CMH) test ** DCR: disease control rate

15. CRYSTAL trial: Surgery with curative intent
FOLFIRI alone Cetuximab + FOLFIRI
ITT population (pre-planned)
Liver metastases only population (exploratory)
4.5
9.8 1 2 3 4 5 6 7 8 9 10
Percentage (%)
n=134 / n=122
No residual tumor in patients
with liver metastases
p=0.0034*
odds ratio 3.0
[95% CI: ]
n=599 / group
n=599 / group
*CMH test

16. Progression-free survival time (months)
CRYSTAL trial: Primary endpoint PFS subgroup: liver metastases only
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cetuximab + FOLFIRI, n=122
FOLFIRI, n=134
HR = 0.637; 95% CI = [ ]
Stratified log-rank p-value = 0.023
11.4 mo
PFS estimate
9.2 mo 2 4 6 8 10 12 14 16 18 20
Subjects at risk
Progression-free survival time (months)
FOLFIRI alone
134
115 93 68 36 18 6 3 7 4 1
Cetuximab +
FOLFIRI
122
100 84 74 51 26 15 6 2 1 1

17. CRYSTAL trial: PFS time subgroup analyses
HR [95% CI]
All ITT subjects (n=1198)
0.851 [ ]
Subgroup (number of patients)
Age
< 65 years (n=751)
0.775 [ ]
≥ 65 years (n=446)
0.989 [ ]
ECOG Performance Status
0,1 (n=1156)
0.839 [ ]
2 (n=42)
1.187 [ ]
Involved disease sites
≤ 2 (n=1016)
0.862 [ ]
> 2 (n=166)
0.794 [ ]
Liver metastases only
Yes (n=256)
0.637 [ ]
No (n=942)
0.913 [ ]
Prior adjuvant therapy
Yes (n=243)
0.816 [ ]
No (n=955)
0.858 [ ]
Leucocytes
> 10000/mm3 (n=214)
0.765 [ ]
See Lewis et al. BMJ Jun 16;322(7300): PubMed-ID:
≤ 10000/mm3 (n=943)
0.874 [ ]
Alkaline Phosphatase
≥ 300 U/L (n=151)
0.819 [ ]
< 300 U/L (n=986)
0.836 [ ]
LDH
> UNL (n=540)
0.790 [ ]
≤ UNL (n=516)
0.956 [ ]
0.1
0.2
0.5 1 2 5 10
Favors Cetuximab+FOLFIRI
Favors FOLFIRI

18. Progression-free survival time (months)
CRYSTAL trial: Subgroup analysis of PFS time by on-study skin reactions: cetuximab + FOLFIRI
Skin reaction grade 0 or 1, n=244
*There were no grade 4 skin reactions
0.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0
Progression-free survival time (months)
1.00
0.75
0.50
0.25
0.00
PFS estimate
Skin reaction grade 2, n=243
Skin reaction grade 3*, n=112
11.3 mo
5.4 mo
9.4 mo

19. CRYSTAL trial: Treatment exposure
5-FU
Irinotecan
Cetuximab
FOLFIRI
alone
n=602
Cetuximab + FOLFIRI
n=600
FOLFIRI alone
Median duration of treatment, weeks
25.4
26.0
25.6
25.0
Median number of infusions [range] 12
[0 - 47]
[0 - 41]
[1 - 47] 24
[1 - 88]
Relative dose intensity
≥ 80%,% 92 88 78 74 81
Dose reduction
≥ 1 level, % 10 20 25 11
Dose delay
≥ 9 days, % 56 58 55 51

20. CRYSTAL trial: Conclusions (1)
The CRYSTAL trial met its primary objective of demonstrating that the addition of cetuximab to FOLFIRI in the first-line treatment of EGFR-detectable mCRC significantly increased PFS
There was a 15% risk reduction for progression in patients treated with cetuximab plus FOLFIRI compared to FOLFIRI

21. CRYSTAL trial: Conclusions (2)
The addition of cetuximab to FOLFIRI was associated with:
Higher response rates (p=0.0038)
Threefold higher R0 resection rates for initially unresectable disease (p=0.0034)
Patients with liver metastases as the only disease site achieved a longer PFS than the whole population
Skin reactions showed a strong correlation with efficacy

22. CRYSTAL trial: Conclusions (3)
Treatment was generally well-tolerated
Neutropenia and febrile neutropenia were similar in both groups
Grade 3/4 diarrhea was more frequent with the combination
Skin toxicity was in the expected range
All cause mortality 60-days-after-treatment-start and 30-days-after-treatment-stop was similar in both groups
No cetuximab-related deaths

23. CRYSTAL trial: Conclusions (4)
Survival follow-up, QoL and molecular marker evaluation is ongoing

24. 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